bims-ginsta Biomed News
on Genome instability
Issue of 2026–03–22
47 papers selected by
Jinrong Hu, National University of Singapore
  1. Organizing chromosomes in oocytes and embryos.
  2. Ca²⁺ leakage is a conserved signal for non-canonical ATG8/LC3 lipidation and membrane repair.
  3. A single cluster of RNA Polymerase II molecules is stably associated with active genes.
  4. TBP regulates transposable element expression in early mouse embryos.
  5. Polar chromosomes are rescued from missegregation by spindle elongation-driven microtubule pivoting.
  6. The Dynamics of Chromatin Replication.
  7. ER-tethering directs TREX1 penetration of a BAF-dependent barrier at micronuclei.
  8. Two translocation mechanisms drive neural stem cell dissemination into the human fetal cortex.
  9. Primordial germ cells experience increasing physical confinement and DNA damage during migration in the mouse embryo.
  10. MFF budding from mitochondria regulates melanosome size and maturation.
  11. Multi-omic analyses reveal a differential contribution of chromatin-associated PP1 holoenzymes to mitotic exit and G1 re-establishment.
  12. Kinase KEY1 controls pyrenoid condensate size throughout the cell cycle by disrupting phase separation interactions.
  13. LncRNA-splicing factor condensates regulate hypoxia-responsive pre-mRNA processing near nuclear speckles.
  14. A cell cycle-dependent transition of acetylation to phosphorylation regulates timely centrosome maturation.
  15. Functional chromatin signatures premark future lineage-specific enhancers.
  16. Microtubule end stabilisation by cooperative oligomers of Ska and Ndc80 complexes.
  17. Molecular basis of oocyte cytoplasmic lattice assembly.
  18. Fructose-1,6-bisphosphate couples glycolytic activity to cell adhesion.
  19. Unstructured transcription factor interactions enable emergent specificity.
  20. AP-1 mediates cellular adaptation and memory formation.
  21. Mitochondrial Precursor Overaccumulation Stress.
  22. RHOT Proteins Link Mitochondrial Motility to Cardiomyocyte Sarcomere Maturation.
  23. Fine-tuning ERK activity enables proliferation-differentiation balance during lineage specification of human embryonic stem cells.
  24. Regulation of adult stem cells by Niche-sensing cellular protrusions.
  25. Arp2/3-dependent actin assembly shapes endosomes and promotes intracellular trafficking in fission yeast.
  26. Microhomology-mediated end joining acts directly on replication forks to repair single-ended double-strand breaks.
  27. The Promoter-Proximal Pause: A Decision Point Governing RNA Polymerase II Fate.
  28. Phase separation of DUX family proteins drives totipotent-like state via 3D genome reorganization and retrotransposon activation.
  29. Activation and regulation of the dynein-dynactin-NuMA complex.
  30. Species-specific roles of SP1 in bovine and human embryonic genome activation and early embryonic development.
  31. Mitochondrial control of glycerolipid synthesis by a PEP shuttle.
  32. Condensate-mediated shape transformations of cellular membranes by capillary forces.
  33. Single-molecule peptide sequencing through reverse translation of peptides into DNA.
  34. Hijacking ERAD for targeted degradation of transmembrane proteins.
  35. Stage-specific transcriptomics of a leader cell reveals cell machineries driving collective invasion.
  36. The Dynamic Landscape of Alternative 3' UTR during Mammalian Preimplantation Development.
  37. Phosphorylation and DNA damage resolution coordinate SOX2-mediated reprogramming in vivo.
  38. Transcription factor NFYA directs male meiotic entry by regulating accessible chromatin at meiotic promoters in mice.
  39. Single-nucleus epigenomic profiling of the adult human central nervous system unveils epigenetic memory of developmental programs.
  40. The E3 ubiquitin ligase mechanism specifying targeted microRNA degradation.
  41. SEL1L-HRD1 ERAD-autophagy interplay maintains mitochondrial homeostasis in brown adipocytes.
  42. Mechanisms of lung regeneration and repair.
  43. Replication origin flexibility: a tool to mitigate the hazards of excess replication.
  44. Control of the signaling of RAS proteins by modulating their palmitoylation.
  45. A genetically encoded fluorescent sensor for monitoring spatiotemporal prostaglandin E2 dynamics in vivo.
  46. Synthetic circuits for cell ratio control.
  47. ESCRT-Mediated Machinery Directly Drives Cardiac T-Tubule Formation.
  1. Curr Top Dev Biol. 2026 ;pii: S0070-2153(26)00015-3. [Epub ahead of print]166 121-133
    Organizing chromosomes in oocytes and embryos.
    Blake Hernandez, Nicolas Plachta.
      Faithful chromosome segregation emerges from the mutual cooperation of chromosomes and spindle microtubules. Textbook models of mitosis traditionally emphasize centrosome-driven spindle formation and chromosome capture. However, early mammalian development proceeds under constraints which are incompatible which a centrosome-driven model. Here, we briefly review the non-standard mechanisms of chromosome organization operating during early mouse development. We propose that these mechanisms, despite their differences, reflect a conserved set of organizational principles adapted to distinct developmental contexts.
    Keywords:  Actin; Cell division; Cytoskeleton; Meiosis; Microtubules; Mitosis
    DOI:  https://doi.org/10.1016/bs.ctdb.2026.01.015
  2. EMBO J. 2026 Mar 20.
    Ca²⁺ leakage is a conserved signal for non-canonical ATG8/LC3 lipidation and membrane repair.
    Di Chen, Antony Fearns, Christopher J Peddie, Maximiliano G Gutierrez.
      Endomembrane damage of intracellular vesicles triggers signals that activate membrane repair in mammalian cells to restore homeostasis. However, the signals that drive diverse membrane repair recruitment at the individual organelle level are unknown. Here by recording Ca2+ leakage history with a newly developed Ca2+ probe in human macrophages, we discovered that Ca²⁺ leakage serves as a conserved signal that triggers ATG8/LC3 lipidation after different types of sterile membrane damage. The damaged compartments consisted of both single membrane and multilayered membrane structures undergoing extensive membrane remodelling. We show the complexity and acidification of these ATG8/LC3-positive compartments depends on the nature of the membrane damage trigger. Functionally, the formation of these multimembrane ATG8/LC3-positive compartments restricted membrane damage independently of canonical autophagy and the recruitment of ESCRT components CHMP2A/CHMP4B. Altogether, we show that endolysosomal Ca²⁺ leakage triggers non-canonical LC3 lipidation on damaged membranes to promote membrane repair in human macrophages.
    Keywords:  Ca2+ Leakage; Lysosome Damage; Macrophages; Membrane Repair; Non‑canonical LC3 Lipidation
    DOI:  https://doi.org/10.1038/s44318-026-00741-z
  3. Nat Commun. 2026 03 20. pii: 2580. [Epub ahead of print]17(1):
    A single cluster of RNA Polymerase II molecules is stably associated with active genes.
    Apratim Mukherjee, Manya Kapoor, Kareena Shankta, Samantha Fallacaro, Raymond D Carter, Gabriela Hayward-Lara, Puttachai Ratchasanmuang, Yara I Haloush, Mustafa Mir.
      In eukaryotic nuclei, transcription is associated with the clustering of RNA Polymerase II (RNAPII) molecules. The mechanisms underlying cluster formation, their interactions with genes, and their impact on transcriptional activity remain heavily debated. Here, we take advantage of the naturally occurring increase in transcriptional activity during Zygotic Genome Activation (ZGA) in Drosophila melanogaster embryos to characterize the functional roles of RNAPII clusters in a developmental context. Using single-molecule tracking and lattice light-sheet microscopy, we find that RNAPII cluster formation depends on transcription initiation and that cluster lifetimes depend on transcriptional activity when not constrained by interphase duration. We show that single clusters are stably associated with active gene loci during transcription and that cluster intensities are strongly correlated with transcriptional output. Collectively, our data and simulations on cluster formation kinetics show that RNAPII clusters reflect local accumulations of transcriptionally engaged polymerases and do not form through higher-order mechanisms such as phase separation.
    DOI:  https://doi.org/10.1038/s41467-026-70775-8
  4. EMBO J. 2026 Mar 20.
    TBP regulates transposable element expression in early mouse embryos.
    Clara Hermant, Carlos Michel Mourra-Díaz, Marlies E Oomen, Natasha Jansz, Camille Noll, Antoine Canat, Mrinmoy Pal, Tsunetoshi Nakatani, Tamas Schauer, Maria-Elena Torres-Padilla.
      The activation of the embryonic genome is a crucial step in development. In addition to thousands of genes, many transposable elements (TEs) are robustly transcribed during early mammalian development. However, their transcriptional regulators remain largely unexplored. Here, we set out to identify transcription factors regulating the expression of TEs from the LINE, SINE and ERVL families during mouse preimplantation development. In particular, the MaLR family are the most abundant ERVL in the mouse genome and are also the most abundant constituent of the transcriptome in early mouse embryos. We find that the general transcription factor TBP binds and activates MaLRs in mouse embryos. Loss-of-function of TBP leads to downregulation of MaLRs, specifically the ORR1A family, which is the youngest ORR subclass and contributes a significant portion of major zygotic genome activation transcripts. Our work identifies regulators of TE expression in vivo and highlights a previously unrecognised role for the general transcription factor TBP in regulating a highly specific TE transcriptional programme.
    Keywords:  ERVL; MaLR; Mouse Embryos; Retrotransposons; TBP
    DOI:  https://doi.org/10.1038/s44318-026-00736-w
  5. Nat Commun. 2026 03 17. pii: 2049. [Epub ahead of print]17(1):
    Polar chromosomes are rescued from missegregation by spindle elongation-driven microtubule pivoting.
    Isabella Koprivec, Valentina Štimac, Mario Đura, Kruno Vukušić, Petra Mikec, Iva M Tolić.
      Polar chromosomes, which initially attach to the mitotic spindle behind the pole, are prone to missegregation and micronuclear entrapment, contributing to chromosomal instability in cancer. Yet, the mechanisms ensuring their faithful segregation remain unclear. Here, we show that polar chromosomes require a unique step involving spindle elongation, which repositions chromosome-bound astral microtubules by pivoting them around the centrosome toward the spindle surface. By modulating Eg5/KIF11 activity, we demonstrate that spindle elongation determines the direction and extent of pivoting, with microtubules from the opposite spindle half facilitating final movement. Kinetochores on polar chromosomes form mono-lateral attachments, recruiting corona components and partially Mad2, but lacking Astrin. In cancer cell lines, limited spindle elongation delays polar chromosome resolution, whereas enhanced elongation accelerates it. These findings highlight the role of spindle elongation in the timely rescue of chromosomes from the "danger zone" behind the pole, providing mechanistic insight into chromosome congression errors in cancer.
    DOI:  https://doi.org/10.1038/s41467-026-69830-1
  6. Annu Rev Biochem. 2026 Mar 20.
    The Dynamics of Chromatin Replication.
    Leonie Kollenstart, Sebastian Jespersen Charlton, Anja Groth.
      The ability of cells to transmit information encoded in the genome, and its organization into chromatin across cell generations, is a cornerstone of eukaryotic life. Chromatin replication, the copying of the mammalian genome in its structural and functional chromatin context to maintain cell identity and fate, is fundamental to lifelong health and has important implications for cancer and aging. Here, we review the major breakthroughs in our understanding of chromatin dynamics during DNA replication, critical for genome and epigenome inheritance. We discuss how chromatin is disrupted at the replication fork and how the replication machinery ensures transmission of parental histones with their modifications to daughter DNA strands with high fidelity. We highlight how incorporation of new histones is integrated into this process to maintain chromatin integrity and functionality. Finally, we consider how these processes maintain gene expression programs and thus cellular identity and function across cell division throughout the organismal life span.
    DOI:  https://doi.org/10.1146/annurev-biochem-082525-050024
  7. Mol Cell. 2026 Mar 19. pii: S1097-2765(26)00126-7. [Epub ahead of print]86(6): 1099-1115.e10
    ER-tethering directs TREX1 penetration of a BAF-dependent barrier at micronuclei.
    Yanyang Chen, Roshan Xavier Norman, Eléonore Toufektchan, Xiaohan Luan, Abraham Shim, Hannah Rosenberg, Marton Tibor Kovacs, Ashley Nichols, James Hickling, Paolo Cifani, Alex Kentsis, Wen Zhou, John Maciejowski.
      Micronuclei are membrane-encapsulated nuclear aberrations that form following chromosome segregation errors. Micronuclear membrane collapse permits access of the pattern recognition receptor cGAS and its antagonist, the TREX1 exonuclease. TREX1 endoplasmic reticulum tethering is essential for invasion into ruptured micronuclei, but the mechanisms underlying this dependency are unknown. Here, we identify BAF as a key regulator of TREX1 activity at micronuclei. BAF accumulates at micronuclei following membrane collapse and augments TREX1 recruitment via interactions with LEM-domain proteins. Despite delayed entry, TREX1 exhibits enhanced micronuclear DNA degradation and independence from ER-tethering in BAF-deficient cells. Recombinant BAF inhibits TREX1-mediated DNA degradation in vitro via DNA-binding. BAF similarly outcompetes cGAS for micronuclear DNA and limits cGAS-dependent immune signaling. These findings reveal a BAF-dependent protective barrier to the diffusive entry of DNA-binding proteins into ruptured micronuclei that explains TREX1 ER-tethering requirements for suppressing innate immune responses in chromosomally unstable cells.
    Keywords:  BAF; STING; TREX1; cGAS; chromosomal instability; chromothripsis; micronuclei
    DOI:  https://doi.org/10.1016/j.molcel.2026.02.012
  8. Neuron. 2026 Mar 16. pii: S0896-6273(26)00085-1. [Epub ahead of print]
    Two translocation mechanisms drive neural stem cell dissemination into the human fetal cortex.
    Ryszard Wimmer, Clarisse Brunet Avalos, Pauline Lestienne, Laure Coquand, Amandine Di Cicco, Christophe Chehade, Annasara Artioli, Matthieu Cortes, Anna-Sophie Macé, Xiuyu Wang, Jean-Baptiste Manneville, Bettina Bessière, Ananya Roy, Karin Forsberg-Nilsson, Julia Ladewig, Fabien Guimiot, Alexandre D Baffet.
      The strong increase in the size of the human neocortex is supported by a neural stem cell population, the basal radial glial (bRG) cells. Using live imaging of human fetal tissue and cortical organoids, we identify two translocation mechanisms for bRG cell colonization of the human neocortex. On top of an actomyosin-dependent movement called mitotic somal translocation (MST), we identify a microtubule-dependent motion occurring during interphase that we call interphasic somal translocation (IST). We show that IST is driven by the dynein motor and its activator LIS1, which are recruited to the nuclear envelope by the LINC complex, while MST is controlled by the mitotic cell-rounding pathway. Eighty-five percent of bRG cell translocation is due to IST, resulting in a total movement of 0.67 mm per month of gestation. Our work identifies how bRG cells colonize the human fetal cortex and further shows that IST and MST also occur in bRG-related glioblastoma cells.
    Keywords:  cell migration; cytoskeleton; fetal tissue; human neocortex development; human neurogenesis; live imaging; neural stem cells; organoids; radial glial cells
    DOI:  https://doi.org/10.1016/j.neuron.2026.02.002
  9. Sci Adv. 2026 Mar 20. 12(12): eaec7919
    Primordial germ cells experience increasing physical confinement and DNA damage during migration in the mouse embryo.
    Katharine Goodwin, Theresa Anne Emrich, Sebastian Arnold, Katie McDole.
      To produce healthy offspring, an organism must pass on its genetic material with high fidelity. In many species, this is accomplished by primordial germ cells (PGCs), which give rise to sperm or eggs. PGCs are often specified far from the future gonads and must migrate through developing tissues to reach them. Failure to do so can result in infertility or germ cell tumors. While PGC migration is well characterized in some species, very little is known about their migration in mammalian embryos. Here, we performed dynamic and quantitative analyses of PGC migration from E7.5 to E9.5 in the mouse embryo, providing the first comprehensive study of the migratory characteristics of PGCs from their point of origin to the gonads. We demonstrate that migrating PGCs are influenced by the surrounding environment and, in contrast to other organisms, extend highly dynamic, actin-rich protrusions to navigate through extracellular matrix (ECM) barriers, and tight intercellular spaces. As PGCs migrate through increasingly confined spaces, they undergo significant nuclear deformation and become prone to nuclear rupture and DNA damage. Their migration under confinement may be aided in part by a depleted nuclear lamina that leads to wrinkled nuclear morphology. Our high-resolution and dynamic imaging approaches have uncovered an unexpected risk to genome integrity in migrating PGCs, with implications for DNA repair and adaptations in nuclear mechanics in PGCs.
    DOI:  https://doi.org/10.1126/sciadv.aec7919
  10. Nat Commun. 2026 Mar 14.
    MFF budding from mitochondria regulates melanosome size and maturation.
    Ana Paula Magalhães Rebelo, Aurora Maracani, Samuele Greco, Federica Dal Bello, Lucia Santorelli, Marco Gerdol, Alberto Pallavicini, Tomas Knedlik, Sara Schiavon, Luca Scorrano, Philip S Goff, Christian Frezza, Elena V Sviderskaya, Paolo Grumati, Marta Giacomello.
      Melanosomes are lysosome-related organelles that produce and accumulate melanin. Their maturation is regulated through interactions with mitochondria and involves the export and recycling of proteins via tubular transport and fission events whose mechanisms are unknown. Here, we demonstrate that the mitochondrial fission factor protein (MFF) is involved in melanosome fission. MFF is trafficked between mitochondria and melanosomes and locates at melanosome fission events. Upon downregulation of MFF, but not of dynamin-related protein 1 (DRP1), melanosomes enlarge, intracellular melanin accumulates, and melanosomal lumenal catabolism increases, indicating that MFF-dependent melanosome fission is required for their maturation. We show that MFF interacts with regulators of the ARP2/3 complex, which drives F-actin nucleation. Actin filaments accumulate between melanosomes at MFF-enriched membrane constriction sites, and silencing of ARP2/3 subunits mimics the increase in melanosome size. MFF regulates actin-dependent fission of melanosomes via the ARP2/3 complex, indicating an extramitochondrial function for MFF in the regulation of melanosome homeostasis.
    DOI:  https://doi.org/10.1038/s41467-026-70572-3
  11. Dev Cell. 2026 Mar 17. pii: S1534-5807(26)00081-X. [Epub ahead of print]
    Multi-omic analyses reveal a differential contribution of chromatin-associated PP1 holoenzymes to mitotic exit and G1 re-establishment.
    Konstantinos Stamatiou, Florentin Huguet, Marta Budzinska, Jose I de Las Heras, Denise Ragusa, Ines J deCastro, Christos Spanos, Juri Rappsilberg, Paola Vagnarelli.
      Mitotic exit is an important part of the cell cycle, requiring the coordination of many chromatin and cytoskeleton remodeling events to successfully complete cell division and maintain cell identity. Protein dephosphorylation is a key step in directing mitotic exit, and protein phosphatase 1 (PP1) is essential to this process; however, the specific contribution of its numerous targeting subunits is still unknown. Here, we have investigated the function of three chromatin-associated PP1-targeting subunits in mitosis exit: Repo-Man, Ki-67, and protein phosphatase 1 nuclear targeting subunit (PNUTS). We generated endogenously tagged, auxin-degradable alleles for each subunit in the human cell line HCT116 and used a multi-omic approach to address their specific contributions toward transcription resumption, chromatin accessibility, and protein dephosphorylation at the transition from mitosis to G1. This approach identified their distinct role in mitotic exit, provided datasets for the cell-cycle community, and highlighted functions for Ki-67 and Repo-Man in genome stability and organization.
    Keywords:  cell-cycle regulation; centromere; mitotic exit; protein phosphatase 1; spindle assembly checkpoiny; transcription resumption
    DOI:  https://doi.org/10.1016/j.devcel.2026.02.016
  12. Nat Cell Biol. 2026 Mar 17.
    Kinase KEY1 controls pyrenoid condensate size throughout the cell cycle by disrupting phase separation interactions.
    Shan He, Linnea M Lemma, Alejandro Martinez-Calvo, Guanhua He, Jessica H Hennacy, Lianyong Wang, Sabrina L Ergun, Ashwani K Rai, Colton Wang, Luke Bunday, Angelo Kayser-Browne, Quan Wang, Clifford P Brangwynne, Ned S Wingreen, Martin C Jonikas.
      Biomolecular condensates spatially organize cellular functions, but the regulation of their size, number, dissolution and re-condensation is poorly understood. The pyrenoid, an algal biomolecular condensate that mediates one-third of global CO2 fixation, typically exists as one large condensate per chloroplast, but during cell division it transiently dissolves and reconfigures into multiple smaller condensates. Here, we identify a kinase, KEY1, in the model alga Chlamydomonas reinhardtii that regulates pyrenoid condensate size and number dynamics throughout the cell cycle and is necessary for normal pyrenoid function and growth. Unlike the wild type, key1 mutant cells have multiple smaller condensates throughout the cell cycle that fail to dissolve during cell division. We show that KEY1 localizes to the condensates and promotes their dissolution by disrupting interactions between their core constituents, the CO2-fixing enzyme Rubisco and its linker protein EPYC1, through EPYC1 phosphorylation. We develop a biophysical model that recapitulates KEY1-mediated condensate size and number regulation and suggests a mechanism for controlling condensate position. These data provide a foundation for the mechanistic understanding of the regulation of size, number, position and dissolution in pyrenoids and other biomolecular condensates.
    DOI:  https://doi.org/10.1038/s41556-026-01908-w
  13. Mol Cell. 2026 Mar 19. pii: S1097-2765(26)00128-0. [Epub ahead of print]86(6): 1061-1080.e10
    LncRNA-splicing factor condensates regulate hypoxia-responsive pre-mRNA processing near nuclear speckles.
    You Jin Song, Min Kyung Shinn, Sushant Bangru, Yu Wang, Qinyu Sun, Qinyu Hao, Pankaj Chaturvedi, Susan M Freier, Pablo Perez-Pinera, Erik R Nelson, Andrew S Belmont, Mitchell Guttman, Supriya G Prasanth, Auinash Kalsotra, Rohit V Pappu, Kannanganattu V Prasanth.
      The alternative splicing (AS) of pre-mRNA regulates key cellular processes, and its dysregulation is linked to tumorigenesis. Hypoxia, a common feature of malignant tumors, triggers AS in thousands of genes. The mechanisms controlling hypoxia-responsive AS remain unclear. We observe that hypoxia-responsive spliced exons exhibit characteristics of inefficient splicing, and the genes encoding these transcripts are pre-positioned near nuclear speckles-the membraneless nuclear bodies that boost splicing. The speckle-enriched long noncoding RNA (lncRNA) MALAT1 (Metastasis-associated lung adenocarcinoma transcript 1), induced during hypoxia, associates with the hypoxia-responsive genes. Furthermore, MALAT1 promotes AS by modulating the interaction between the SR family of splicing factor 1 (SRSF1) and pre-mRNAs. Mechanistically, MALAT1 promotes the condensation of SRSF1, and the condensates are preferentially recognized and recruited by RNA polymerase II (RNAPII). Overall, our results demonstrate that MALAT1 dictates hypoxia-induced AS by organizing splicing factor condensates near speckles to enable the efficient RNAPII-mediated recruitment of splicing factors to pre-mRNAs.
    Keywords:  RNA splicing; RNA-binding protein; breast cancer; gene regulation; nuclear domains; nuclear organization; phase separation
    DOI:  https://doi.org/10.1016/j.molcel.2026.02.014
  14. Nat Commun. 2026 03 20. pii: 2583. [Epub ahead of print]17(1):
    A cell cycle-dependent transition of acetylation to phosphorylation regulates timely centrosome maturation.
    Jimin Li, Jianqiang Liang, Guifang Chen, Xuejie Wang, Yanyan Wang, Jingfei Zhan, Yunjing Guo, Jiadong Wang, Xuefeng Chen.
      Centrosomes must undergo maturation in the G2/M phases to activate the microtubule-organizing activity, ensuring proper bipolar spindle assembly and chromosome segregation. Polo-like kinase 1(PLK1) is crucial for centrosome maturation. How the cell cycle controls timely PLK1 recruitment and centrosome maturation remains elusive. Here, we find that the ubiquitin E3 ligase RNF40 localizes to centrosomes and is phosphorylated by CDK1 on T529/T557 in the G2/M phases. This phosphorylation primes its binding to PLK1 and promotes timely PLK1 recruitment and centrosome maturation, establishing the CDK1-RNF40-PLK1 cascade as a mechanism controlling centrosome maturation. We also find that RNF40 is acetylated in interphase and undergoes an acetylation-to-phosphorylation transition in late G2 and M phases, which permits timely activation of the CDK1-RNF40-PLK1 cascade. Constitutive RNF40 acetylation or deficient RNF40 phosphorylation impairs PLK1 localization, microtubule nucleation, and bipolar spindle assembly, causing mitotic catastrophe. Thus, the cell cycle-dependent transition of RNF40 modifications ensures timely centrosome maturation and chromosome segregation.
    DOI:  https://doi.org/10.1038/s41467-026-70271-z
  15. Cell Genom. 2026 Mar 18. pii: S2666-979X(26)00051-0. [Epub ahead of print] 101189
    Functional chromatin signatures premark future lineage-specific enhancers.
    Julian Pulecio, Zakieh Tayyebi, Dingyu Liu, Wilfred Wong, Renhe Luo, Jeyaram R Damodaran, Samuel J Kaplan, Nan Hu, Hyein S Cho, Jielin Yan, Dylan Murphy, Robert W Rickert, Abhijit Shukla, Aaron Zhong, Denis Torre, Qianzi Li, Federico González, Dexin Yang, Wenbo Li, Ting Zhou, Effie Apostolou, Christina S Leslie, Danwei Huangfu.
      It remains unknown whether early embryonic cells harbor a blueprint for future enhancers that regulate the expression of lineage-specific genes in adult tissues. Here, we demonstrate that embryonic stem cells (ESCs) have transcriptionally competent chromatin regions (CCRs) prepared to induce the expression of lineage genes prior to differentiation. CCRs represent activatable pre-enhancers within the topological chromatin domains of lineage genes, marked by chromatin signatures distinguishable from primed/poised enhancers, enabling their genome-wide identification. The pioneer transcription factor (TF) FOXA2 preferentially binds CCRs during early lineage specification, promoting their conversion into active enhancers. CCRs can be harnessed to boost the expression of master TFs and promote the direct reprogramming of ESCs into differentiated cells, showcasing their potential for practical applications. Our findings identify a mechanism by which ESCs rapidly establish enhancer activity during early lineage differentiation and expand our understanding of the epigenetic features supporting transcriptional regulation and cellular plasticity.
    Keywords:  CRISPR; chromatin; developmental competence; embryonic stem cells; epigenetics; gene regulation; lineage specification; pluripotency
    DOI:  https://doi.org/10.1016/j.xgen.2026.101189
  16. EMBO J. 2026 Mar 20.
    Microtubule end stabilisation by cooperative oligomers of Ska and Ndc80 complexes.
    Renjith M Radhakrishnan, Lauren Stokes, Matthew Day, Pim J Huis In 't Veld, Vladimir A Volkov.
      During mitosis, properly aligned chromosomes stabilise microtubule ends with the help of kinetochores to ensure timely segregation of chromosomes. Microtubule-binding components of the human outer kinetochore, such as Ndc80 and Ska complexes, are present in multiple copies and together bind several microtubule ends, creating a highly multivalent binding interface. Whereas Ndc80:Ndc80 and Ndc80:microtubule binding is crucial for interface stability, Ndc80 alone in absence of Ska is unable to support stable kinetochore-attachments. Using cryo-electron tomography, we demonstrate that oligomeric Ndc80:Ska assemblies stabilise microtubule ends against shortening by strengthening lateral contacts between tubulin protofilaments at microtubule plus-ends. We further identify a point mutation within the SKA1 microtubule-binding domain that does not affect microtubule-binding of individual Ska molecules, but does abolish Ska:Ska interactions. Finally, we report that oligomerisation of Ska, in a cooperative fashion together with the Ndc80, is necessary to maintain stable microtubule attachments both in vivo and in vitro.
    Keywords:  Kinetochore; Microtubule; Mitosis; Ndc80; Ska
    DOI:  https://doi.org/10.1038/s44318-026-00749-5
  17. Nature. 2026 Mar 17.
    Molecular basis of oocyte cytoplasmic lattice assembly.
    Shuxian Liu, Yusong Liu, Junchao Xue, Zhenzhen Li, Yan Zhang, Bailun Li, Lidan Xu, Lili Li, Zhenzhen Yu, Hongtao Yu, Haishan Gao, En-Zhi Shen.
      Mammalian oocytes are filled by fibric structure called cytoplasmic lattice (CPL), essential for oocyte maturation and early embryonic development1-3. CPL comprises subcortical maternal complex (SCMC) and multiple components, including PADI62,4,5. Despite its discovery in the 1960s, the molecular architecture and assembly mechanisms of CPL have remained poorly understood. Here we present the cryo-electron microscopy (cryo-EM) structure of the CPL isolated from mouse oocytes. Our analysis identified 14 constitutive protein subunits and revealed that CPL is composed of repeating "U-shaped basket" (UB) and "adapter ring" (AR)- featured units, forming a filamentous architecture. AR adopts a two-fold symmetric conformation, containing two NLRP4f, four SCMC and two ZBED3 subunits circularized via two distinct interaction clusters. The UB is anchored by PADI6, a didecamer composed of ten homodimers assembled by two back-to-back pentamers, each forming the lateral side of UB. The underfoot base and up-down sides of the UB are formed by multiple central-symmetric assemblies (UBE2D3-UHRF1-NLRP14) and (TUBB2B-TUBB2A-FBXW24-SKP1) respectively, associating with the PADI6 pentamers to construct the intact UB structure. Two SCMC dimer within each AR connect the up and down sides of two adjacent UBs with an extensive protein-protein interaction network and thus maintain the repetitive connection between the neighboring CPL units. Our work unveils the architectural principles underlying the assembly of this large, periodic CPL filament, offering a molecular basis for understanding CPL's functions in early mammalian embryogenesis and female reproductive disorders.
    DOI:  https://doi.org/10.1038/s41586-026-10360-7
  18. Nat Cell Biol. 2026 Mar 16.
    Fructose-1,6-bisphosphate couples glycolytic activity to cell adhesion.
    Lennart Hoffmann, Marlen Duchmann, Katina Lazarow, Yun-Hsuan Huang, Fabian Lukas, Wen-Ting Lo, Regina Feil, Christopher Schmied, Martin Lehmann, John E Lunn, Ilaria Piazza, Jens P von Kries, Volker Haucke, Tanja Maritzen.
      Cellular adhesion to the extracellular matrix is essential for morphogenesis, tissue integrity and survival signalling. The best understood adhesion structures are focal adhesions (FAs). In spite of their importance, our knowledge of upstream factors that integrate FA dynamics with other cellular processes, such as metabolism, remains fragmentary. Using a genome-wide screen, we identify aldolase A, a key glycolytic enzyme that converts fructose-1,6-bisphosphate (FBP), as a regulatory switch that links metabolic flux to FA assembly and cell morphogenesis. We show that cellular FBP serves as a signalling metabolite, which transmits information about the metabolic cell state to the actin-based machinery for cell adhesion and protrusion. This mechanism involves FBP binding to the Rac1 inhibitor RCC2 and a concomitant elevation of Rac1 activity resulting in actin reorganization, increased FA assembly and elevated protrusive activity. Here we predict this mechanism to be crucial for processes ranging from development to cancer.
    DOI:  https://doi.org/10.1038/s41556-026-01911-1
  19. Science. 2026 Mar 19. eaeb6487
    Unstructured transcription factor interactions enable emergent specificity.
    Abrar A Abidi, Claudia Cattoglio, Natalie N Tang, Vinson B Fan, Gina M Dailey, Amir D Hay, Prasanthi Kunamaneni, Daniel E Milkie, Xavier Darzacq, Eric Betzig, Robert Tjian, Thomas G W Graham.
      How intrinsically disordered regions (IDRs) influence chromatin binding and nuclear organization of transcription factors (TFs) remains unclear. We employed proximity-assisted photoactivation (PAPA), a single-molecule protein-protein interaction sensor, to investigate how IDRs might influence TF interactions with each other and with chromatin in live cells. We found that the Sp1 DNA binding domain (DBD) interacted poorly with chromatin and did not colocalize with Sp1. Weak interaction of the isolated IDR with full-length Sp1 was enhanced by fusion to various unrelated DBDs. Live imaging of Drosophila polytene chromosomes confirmed that an IDR could confer sharp locus specificity on an otherwise nonspecific DBD. These findings suggest that TF specificity emerges on chromatin when ensembles of diverse, unstructured interactions are scaffolded by transient DNA contacts.
    DOI:  https://doi.org/10.1126/science.aeb6487
  20. Nat Commun. 2026 Mar 20.
    AP-1 mediates cellular adaptation and memory formation.
    Jingxin Li, Pavithran T Ravindran, Aoife O'Farrell, Gianna T Busch, Ryan H Boe, Zijian Niu, Sean Woo, Margaret C Dunagin, Naveen Jain, Yogesh Goyal, Kavitha Sarma, Meenhard Herlyn, Arjun Raj.
      Cellular responses to environmental stimuli are typically thought to be governed by genetically encoded programs. We demonstrate that cancer cells can form and maintain cellular memories when becoming drug resistant, exhibiting characteristics of cellular learning that are dependent on the transcription factor AP-1. We show that cells exposed to a low dose of therapy adapt to become resistant to a high dose, demonstrating that cells can adapt during this time of stress. The application of therapy itself results in the encoding of transient gene expression into cellular memory and that this encoding occurs for both transiently induced and probabilistically arising expression. Chromatin accessibility shows concomitant persistence. A two-color AP-1 reporter system shows that these memories are encoded in cis, constituting an example of activating cis epigenetics. Our findings establish the formation and maintenance of cellular memories as a critical aspect of gene regulation during the development of therapy resistance.
    DOI:  https://doi.org/10.1038/s41467-026-70862-w
  21. Annu Rev Biochem. 2026 Mar 20.
    Mitochondrial Precursor Overaccumulation Stress.
    Liam P Coyne, Xin Jie Chen.
      Damage to mitochondria imparts multifaceted cellular stress that extends beyond bioenergetic deficit. One newly emerged example is mitochondrial precursor overaccumulation stress (mPOS). mPOS is marked by impaired mitochondrial protein import, causing the toxic accumulation and aggregation of unimported mitochondrial precursor proteins in the cytosol. Analogous to the well-studied endoplasmic reticulum stress, which blocks proteins from leaving the cell, mPOS can impose a drastic proteostatic burden in the cytosol and closely interconnects with cell signaling pathways. Here, we review how researchers discovered mPOS and discuss its central importance in several major mitochondria-induced stress signaling pathways. We then focus on the emerging field of mPOS in cell demise and human disease, and we present recent evidence that mPOS can affect cell fitness and survival independent of bioenergetics. Looking forward, mPOS may provide a complementary or alternative pathogenic mechanism to bioenergetic deficit for classic mitochondriopathy and many aging-associated degenerative diseases involving mitochondrial stress.
    DOI:  https://doi.org/10.1146/annurev-biochem-051424-061016
  22. Circ Res. 2026 Mar 16.
    RHOT Proteins Link Mitochondrial Motility to Cardiomyocyte Sarcomere Maturation.
    Natali Froese, Ivanna Shymotiuk, Alexander Froese, Felix Polten, Jonas Jablinski, Tim Scholz, Mortimer Korf-Klingebiel, Christopher Werlein, Paolo Galuppo, Anna Gigina, Katharina Wihler, Johanna Schneider, Sergej Erschow, Maren Heimerl, Malgorzata Szaroszyk, Jan Hegermann, Christoph Wrede, Theresa Schweitzer, Andreas Pich, Robert Geffers, Melanie Ricke-Hoch, Mark P Kühnel, Danny D Jonigk, Adam R Wende, E Dale Abel, Viacheslav O Nikolaev, Kai C Wollert, Johann Bauersachs, Christian Riehle.
       BACKGROUND: Cardiomyocyte mitochondria align with sarcomeres during heart development. Mitochondrial motility is controlled by RHOT (ras homolog family member T) 1 and RHOT2. RHOT1 and RHOT2 are atypical Rho-like small GTPases that are anchored to the outer mitochondrial membrane and couple mitochondria to kinesin and dynein motors. We hypothesized that RHOT protein expression and mitochondrial motility are required for mitochondrial positioning during cardiomyocyte development.
    METHODS: We generated mice with cardiomyocyte-selective deletion of Rhot1 and Rhot2 during embryogenesis (cRhot1/2-KO [constitutive and embryonic cardiomyocyte-selective Rhot1/2 knockout]) or tamoxifen-inducible deletion in the adult heart (iRhot1/2-KO [inducible cardiomyocyte-selective Rhot1/2 knockout mice]) to assess the importance of mitochondrial motility during and after cardiomyocyte maturation. Mitochondrial motility was determined by a motor protein-driven single mitochondria motility assay. Respiratory capacity was measured in isolated mitochondria. Intracellular mitochondrial localization and ATP production in isolated cardiomyocytes were assessed by confocal microscopy and after adenoviral expression of the fluorescence resonance energy transfer-based ATP biosensor ATeam. Cardiac ultrastructure was assessed by electron micrographs; mass spectrometry was used for proteome analysis.
    RESULTS: cRhot1/2-KO mice developed fatal cardiomyopathy associated with sarcomere disarray and perinuclear accumulation of mitochondria and ATP production. Mitochondria isolated from cRhot1/2-KO hearts exhibited impaired motility but preserved respiratory capacity. Mechanistically, proteome analysis identified that RHOT proteins bind mitochondria to contractile muscle fiber proteins. In contrast, inducible deletion of Rhot1 and Rhot2 in adult iRhot1/2-KO mice did not result in heart failure. Despite impaired motility of isolated mitochondria, intracellular mitochondrial localization, local ATP production, and sarcomere structure were preserved in adult iRhot1/2-KO hearts after cardiomyocyte maturation.
    CONCLUSIONS: RHOT proteins bind mitochondria to contractile muscle fiber proteins and are required for mitochondrial positioning in cardiomyocytes during development. Our study links mitochondrial motility and local ATP production to structural and functional maturation of the heart.
    Keywords:  heart failure; mitochondria; myocytes, cardiac; proteome; sarcomere
    DOI:  https://doi.org/10.1161/CIRCRESAHA.125.327297
  23. PLoS Biol. 2026 Mar 17. 24(3): e3003711
    Fine-tuning ERK activity enables proliferation-differentiation balance during lineage specification of human embryonic stem cells.
    Chenyang Ma, Weikang Meng, Jinghan Huang, Wanling Zheng, Xiao Xu, Tao Cheng, Zhengyi Li, Yang Liu, Hao Shen, Feng He, Alessandro Esposito, Pengfei Xu, Ashok Venkitaraman, Jun Ma, Heng Xu, Hongqing Liang.
      ERK is a key signaling mediator controlling both proliferation and lineage specification during embryo development. How ERK choreographs differentiation and proliferation to achieve balanced developmental outcomes in lineages with variable ERK activities remains unclear. To investigate this, we established multiplex quantitative live-cell imaging to track human pluripotent stem cell differentiation into mesendoderm (ME), a lineage specified by gastrulation morphogens and dependent on high ERK activity. We found that distinct morphogen combinations generate varying ERK activity levels, which correlate with heterogeneous ME fate choices despite relatively uniform cell cycle dynamics. To dissect how heterogenous ERK levels directly modulate and coordinate ME differentiation and proliferation, we engineered a synthetic spectrum of titrated ERK activities. Our results showed that ERK fine-tunes ME differentiation potential and cell division speed under nonoverlapping activity ranges, enabling quantitative control of ME fate specification without major effect on cell cycle progression. Mechanistically, this uncoupling stems from differential transcriptional and translational sensitivities of ME-specifying genes versus cell cycle genes to ERK input. Together, our findings reveal how a single signaling pathway quantitatively balances differentiation and proliferation during lineage commitment and embryogenesis.
    DOI:  https://doi.org/10.1371/journal.pbio.3003711
  24. Curr Top Dev Biol. 2026 ;pii: S0070-2153(25)00098-5. [Epub ahead of print]166 101-120
    Regulation of adult stem cells by Niche-sensing cellular protrusions.
    Robert S Krauss, Hsiao-Fan Lo.
      Adult stem cells maintain homeostatic tissue turnover or remain quiescent until tissue injury in a manner dependent on signaling cues from their niche. How stem cells physically interact with niche cells, and whether stem cells possess morphologies that optimize niche recognition and signal reception, is understudied. Here, we discuss several different adult stem cell types in Drosophila and mice that display distinctive morphologies, notably several types of cellular protrusions. Such protrusions function in multiple ways, including: (1) ensuring that the signaling range of ligands secreted by niche cells is restricted only to the stem cell; (2) allowing stem cells to interact simultaneously with multiple, spatially separated, niche cell types; and (3) acting as dynamic sensors of the niche. The in vivo morphology of many adult stem cell types is not well established, and it is likely that cellular protrusions are employed as a means of niche interaction by a variety of such stem cells.
    Keywords:  Cell morphology; Cellular protrusion; Cytoskeleton; Epithelial stem cell; Germline stem cell; Muscle stem cell; Neural stem cell; Stem cell; Stem cell niche
    DOI:  https://doi.org/10.1016/bs.ctdb.2025.10.003
  25. Curr Biol. 2026 Mar 17. pii: S0960-9822(26)00220-4. [Epub ahead of print]
    Arp2/3-dependent actin assembly shapes endosomes and promotes intracellular trafficking in fission yeast.
    Alejandro Melero, Miguel Basante-Bedoya, Olivia Muriel-Lopez, Sophie G Martin.
      Endosomes serve as crucial sorting centers that streamline the distribution of cell surface proteins. The early endosome receives traffic from both the plasma membrane (PM) and the Golgi and orchestrates the redistribution of cargoes for recycling to the PM or through retrograde movement to the Golgi, and for degradation to late endosomes and lysosomes.1 In animal cells and amoebas, Arp2/3-complex-mediated F-actin assembly plays critical roles in many aspects of endosome function, promoting both recycling and degradative trafficking routes.2 Yeast models, which allowed dissection of the major membrane trafficking routes,3 exhibit highly simplified endosomes, as shown in Saccharomyces cerevisiae, where the trans-Golgi network (TGN) functions as recycling endosome.4 Furthermore, there is no reported role for Arp2/3 complex or F-actin in endomembrane remodeling in yeast cells, which lack Arp2/3 complex activators that function on animal endosomes.5,6 Here, we examine the role of the Arp2/3 complex in the shape and function of fission yeast Schizosaccharomyces pombe endosomes. Through live imaging and correlative light electron tomography, we describe endosomes as dynamic tubulo-cisternal compartments, whose morphology requires branched actin, as inhibition of the Arp2/3 complex leads to endosome rounding. Though branched actin primarily localizes to endocytic patches, we show localization of the Arp2/3 complex and F-actin at endosomes for short bursts of time. Remarkably, Arp2/3-dependent actin assembly is critical to allow retrograde trafficking from the endosome to the degradative vacuole. Thus, Arp2/3-complex-dependent actin assembly has a deeply conserved role in shaping and promoting the function of the endomembrane trafficking system.
    Keywords:  Arp2/3 complex; CLEM; F-actin; FM4-64; Schizosaccharomyces pombe; correlative light-electron microscopy; endosome; fission yeast; membrane trafficking; sterol; vacuole
    DOI:  https://doi.org/10.1016/j.cub.2026.02.030
  26. Mol Cell. 2026 Mar 16. pii: S1097-2765(26)00130-9. [Epub ahead of print]
    Microhomology-mediated end joining acts directly on replication forks to repair single-ended double-strand breaks.
    Shibo Li, Yuqin Zhao, Youhang Li, Sameer Bikram Shah, Yanmeng Shi, Tran Nguyen, Zi Wang, Chia-Yu Chang, Anagh Ray, Te-Hsuan Bu, Salvatore Loguercio, Takayo Sasaki, Jonathan H Sussman, Hailong Wang, David M Gilbert, Mirit I Aladjem, Xiaohua Wu.
      Replication stress, intrinsic to oncogenesis, often leads to fork breakage and double-strand break (DSB) formation. Conventionally, break-induced replication (BIR) is considered the primary mechanism for repairing replication-associated single-ended DSBs (seDSBs). Here, we demonstrate that microhomology-mediated end joining (MMEJ) acts directly to repair seDSBs at broken replication forks (fork-MMEJ), preferentially on the leading strands, and functions cooperatively with BIR. While promoted by DNA polymerase theta (Polθ), fork-MMEJ operates independently of MRE11/CtIP-mediated end resection, relies on RPA, and produces asymmetric deletion patterns, distinct from canonical MMEJ (cMMEJ), which is defined at replication-independent double-ended DSBs (deDSBs). ATR, activated as end resection proceeds, serves as a pivotal switch to suppress fork-MMEJ while promoting BIR. The combined inactivation of ATR and Polθ synergistically kills cancer cells under high replication stress with minimal toxicity to normal cells. Together, our study provides fundamental insights into the MMEJ mechanism and offers new strategies for cancer treatment.
    Keywords:  ATR; BIR; MMEJ; PIF1; Polθ; end resection; fork-MMEJ; leading and lagging strands; seDSBs
    DOI:  https://doi.org/10.1016/j.molcel.2026.02.016
  27. Annu Rev Biochem. 2026 Mar 20.
    The Promoter-Proximal Pause: A Decision Point Governing RNA Polymerase II Fate.
    Usman Hyder, David L Bentley.
      A signature feature of transcription on most genes in multicellular animals is that RNA polymerase II (RNAPII) piles up approximately 50 bases downstream of the start site at the promoter-proximal pause (PPP). Promoter-proximal pausing is controlled by positive and negative elongation factors that associate with RNAPII. There are two major outcomes for promoter-proximally paused RNAPII complexes: release into the gene body and premature termination. Here we discuss how RNAPII dynamics at the PPP function in a quality control checkpoint and in regulation of RNAPII flux through genes. We propose a pause release-attenuation model to describe RNAPII dynamics at the PPP.
    DOI:  https://doi.org/10.1146/annurev-biochem-051424-053703
  28. Protein Cell. 2026 Mar 14. pii: pwag014. [Epub ahead of print]
    Phase separation of DUX family proteins drives totipotent-like state via 3D genome reorganization and retrotransposon activation.
    Leilei Gao, Qifeng Gao, Na Hai, Ziqiang Wu, Penghui Li, Han Kang, Xiaohui Song, Jinlian Hua, Shiqiang Zhang, Gang Ren, Jihong Yang, Leqian Yu, Yulei Wei, Junjun Ding, Fan Yang.
      The acquisition of totipotency requires transcriptional activation of endogenous retroviruses (MERVL/HERVL) and zygotic genome activation (ZGA) related genes, yet the molecular mechanisms linking chromatin architecture to this process remain elusive. Here, we demonstrate that mouse Dux and human DUX4, double homeobox transcription factors essential for totipotency, form liquid-liquid phase-separated (LLPS) condensates through conserved arginine residues within intrinsically disordered regions (IDRs) in the Homeobox domain. These condensates recruit CBP/p300 and CTCF to establish super-enhancers (SEs) at MERVL/MT2 loci, enabling H3K27ac deposition and chromatin accessibility. Hi-C analysis revealed that DUX-driven phase separation facilitates 3D genome reorganization, including de novo formation of enhancer-promoter loops and TAD boundary shifts. Disruption of LLPS (DUXR70A) abolished SE assembly, transcriptional activation, and embryonic chimerism. Strikingly, human DUX4 required phase separation for both myotoxic gene activation and cytotoxicity in facioscapulohumeral muscular dystrophy (FSHD) models. Our study establishes a paradigm wherein phase separation integrates transcriptional control with 3D genome remodeling to license totipotency, with direct implications for developmental biology and disease therapy.
    Keywords:  3D genome reorganization; DUX; MERVL; phase separation; super-enhancers; totipotency-like state
    DOI:  https://doi.org/10.1093/procel/pwag014
  29. Nat Chem Biol. 2026 Mar 16.
    Activation and regulation of the dynein-dynactin-NuMA complex.
    Merve Aslan, Ennio A d'Amico, Nathan H Cho, Aryan Taheri, Juan M Perez-Bertoldi, Yuanchang Zhao, Xinyue Zhong, Madeline Blaauw, Andrew P Carter, Sophie Dumont, Ahmet Yildiz.
      During cell division, the nuclear mitotic apparatus protein (NuMA) orchestrates the focusing of microtubule minus-ends in spindle poles and cortical force generation on astral microtubules by interacting with dynein motors, microtubules and other cellular factors. Here we used in vitro reconstitution, cryo-electron microscopy and live-cell imaging to understand the mechanism and regulation of NuMA. We determined the structure of the processive dynein-dynactin-NuMA complex (DDN) and showed that the NuMA N terminus drives dynein motility in vitro and facilitates dynein-mediated transport in live cells. The C terminus of NuMA directly binds and suppresses the dynamics of the microtubule minus-end. Full-length NuMA is autoinhibited for its interactions with dynein and microtubules, whereas mitotically phosphorylated NuMA activates dynein in vitro and interphase cells. Together with dynein, activated full-length NuMA focuses microtubule minus-ends into aster-like structures. These results provide critical insights into the activation of NuMA and dynein for their mitotic functions.
    DOI:  https://doi.org/10.1038/s41589-026-02156-7
  30. Proc Natl Acad Sci U S A. 2026 Mar 24. 123(12): e2526998123
    Species-specific roles of SP1 in bovine and human embryonic genome activation and early embryonic development.
    Hao Jin, Lieying Xiao, Xiaolin He, Bingjie Hu, Yan Shi, Bo Xu, Xiaomei Tong, Shaohua Wang, Panpan Zhao, Lei Luo, Kun Zhang.
      Embryonic genome activation (EGA) marks the onset of the embryonic program and enables the transition toward the first lineage specification. However, the molecular features of EGA and the transcription factors (TFs) orchestrating this process remain unclear. Here, by performing single-cell RNA-seq on bovine embryos, we reveal that major EGA is asynchronously initiated among blastomeres at the 8-cell stage. Integrative analyses reveal distinct protein accumulation compared with transcriptional and translational activation during bovine EGA. Furthermore, we investigate the role of SP1, a TF activated at the minor EGA stage, with motifs enriched in accessible chromatin during the major EGA stage in bovine and human embryos. SP1 deficiency leads to morula arrest in bovine and impairs EGA in human embryos. Multiomics analysis demonstrates that SP1 promotes early lineage gene expression by modulating nearby chromatin states in bovine and directly targets key EGA genes in human embryos. Together, our study delineates the dynamics of bovine EGA and uncovers the conserved and species-specific roles of SP1 in regulating EGA and early development in mammals.
    Keywords:  EGA; SP1; bovine embryo; human embryo; preimplantation
    DOI:  https://doi.org/10.1073/pnas.2526998123
  31. Cell. 2026 Mar 17. pii: S0092-8674(26)00224-2. [Epub ahead of print]
    Mitochondrial control of glycerolipid synthesis by a PEP shuttle.
    Tadashi Yamamuro, Daisuke Katoh, Guilherme Martins Silva, Hiroshi Nishida, Satoshi Oikawa, Yusuke Higuchi, Dandan Wang, Masanori Fujimoto, Naofumi Yoshida, Mark Li, Jihoon Shin, Zezhou Zhao, Jin-Seon Yook, Lijun Sun, Shingo Kajimura.
      Mitochondria provide a variety of metabolites, in addition to ATP, to meet cell-specific needs. One such metabolite is phosphoenolpyruvate (PEP), which contains a higher-energy phosphate bond than ATP and has diverse biological functions. However, how mitochondria-generated PEP is delivered to the cytosol and fulfills cell-specific requirements remains elusive. Here, we show that SLC25A35 regulates mitochondrial PEP efflux and glyceroneogenesis in lipogenic cells that utilize the pyruvate-to-PEP bypass. Reconstitution and structural studies demonstrated PEP transport by SLC25A35 in a pH gradient-dependent manner. Loss of SLC25A35 in adipocytes impaired the conversion of mitochondrial PEP into glycerol-3-phosphate, thereby reducing glycerolipid synthesis. Significantly, hepatic inhibition of SLC25A35 in obese mice alleviated steatosis and improved systemic glucose homeostasis. Together, these results suggest that mitochondria facilitate glycerolipid synthesis by providing PEP via SLC25A35, offering lipogenic mitochondria as a target to limit glycerolipid synthesis, a pivotal step in the pathogenesis of hepatic steatosis and type 2 diabetes.
    Keywords:  bioenergetics; diabetes; glyceroneogenesis; hepatic steatosis; mitochondria; obesity
    DOI:  https://doi.org/10.1016/j.cell.2026.02.017
  32. Proc Natl Acad Sci U S A. 2026 Mar 24. 123(12): e2424126123
    Condensate-mediated shape transformations of cellular membranes by capillary forces.
    Lukas Hauer, Katharina Sporbeck, Joseph F McKenna, Dmytro Puchkov, Alexander I May, Lorenzo Frigerio, Roland L Knorr, Amir H Bahrami.
      Phase-separated biomolecular condensates with liquid-like properties play a key role in the organization and compartmentalization of the intracellular environment. Condensate-mediated capillary forces acting on membranes drive physiologically important reshaping of membrane-bound organelles, such as vacuoles and autophagosomes. Here, we explore condensate-mediated membrane shape transformations. We employ in planta live-cell imaging, an in vitro reconstitution system with tunable interfacial tension, and computer simulations of an elastic membrane model to describe three morphologies of membrane structures localized at condensate interfaces: tubes, sheets, and cups. We find that the forces associated with high interfacial tension drive the formation of stable sheets, while tubes and cups prevail at lower interfacial tension. We calculate the free energies of each membrane shape and identify the energy barriers that govern the transitions between the shapes. With this approach, we find that shape transformations depend on the history of the interfacial membrane and exhibit a tube-to-cup hysteresis. These findings indicate that temporal control of condensate surface properties can mediate the morphogenesis of cup-like structures in cells, such as the formation of "bulbs" within plant vacuoles. Our results further generalize how the interplay of condensates and membranes contributes to intracellular organization.
    Keywords:  Monte Carlo simulation; intracellular wetting; membrane tubule; phase-separated condensates; plant protein storage vacuoles
    DOI:  https://doi.org/10.1073/pnas.2424126123
  33. Nat Biotechnol. 2026 Mar 18.
    Single-molecule peptide sequencing through reverse translation of peptides into DNA.
    Liwei Zheng, Yujia Sun, Linus A Hein, Michael Eisenstein, Hyongsok Tom Soh.
      Despite advances in mass spectrometry and emerging single-molecule approaches, sequencing peptides at the single-molecule level remains a central challenge in proteomics. Here we present a 'reverse translation' strategy that enables single-molecule peptide sequencing with single-amino-acid resolution. In this approach, peptides undergo a modified Edman degradation that iteratively releases N-terminal amino acids tagged with peptide-specific DNA barcodes. Antibody-mediated proximity extension assays identify these barcoded amino acids and generate PCR-amplifiable DNA reporters that record the identity, position and originating peptide of each amino acid. The resulting DNA library is directly read by high-throughput sequencing, converting peptide sequences into digital DNA outputs. Using this approach, we demonstrate true single-molecule peptide sequencing, achieving full sequence coverage in millions of reads and accurate differentiation of both native and post-translationally modified peptides. These results establish a framework that redefines protein sequencing as a DNA sequencing problem and lays the foundation for high-throughput, de novo single-molecule protein sequencing.
    DOI:  https://doi.org/10.1038/s41587-026-03061-z
  34. Cell. 2026 Mar 19. pii: S0092-8674(26)00105-4. [Epub ahead of print]189(6): 1768-1784.e24
    Hijacking ERAD for targeted degradation of transmembrane proteins.
    Haikun Song, Wei Wang, Tingfang Mei, Huiwen Zheng, Keni Ning, Xiaofan Liu, Siulam Cheung, Zhiyuan Cao, Danqi Sheng, Xiaohan Mai, Haoran Zhu, Guankai Guo, Shuaimeng Liu, Rongkai Wei, Qian Wang, Yu Cao, Yu Ding, Yiyan Fei, Rui Liu, Motoyuki Hattori, Chunquan Sheng, Boxun Lu.
      Targeted protein degradation (TPD) technologies provide huge opportunities for drug discovery, but degrading transmembrane (TM) targets remains challenging. Since TM proteins are canonically folded on the endoplasmic reticulum (ER) membrane, we hypothesized that harnessing ER-associated degradation (ERAD) may enable efficient degradation of TM proteins. Here, we established a TPD technology hijacking ERAD and named it ERAD-engaging chimeras (ERADECs), capable of degrading TM targets with high efficacy. We identified desonide as a binder of SYVN1, an ER E3 ligase mediating ERAD. We designed ERADECs targeting programmed death-ligand 1 (PD-L1) by connecting desonide to a known PD-L1 ligand and observed SYVN1- and ERAD-dependent PD-L1 degradation with high efficacy. Functionally, these ERADECs exhibited stronger tumor suppression and PD-L1-lowering effects than a clinically used PD-L1 antibody in vivo. The concept of ERADECs is also expandable to other membrane targets. Collectively, we established a platform technology hijacking ERAD to selectively degrade TM targets with remarkable efficiency.
    Keywords:  E3 ligases; Hrd1; PD-L1; PROTAC; SYVN1; TPD; cancer immune; transmembrane proteins; tumor; ubiquitin
    DOI:  https://doi.org/10.1016/j.cell.2026.01.018
  35. J Cell Biol. 2026 May 04. pii: e202509224. [Epub ahead of print]225(5):
    Stage-specific transcriptomics of a leader cell reveals cell machineries driving collective invasion.
    Priti Agarwal, Iska Maimon Zielonka, Hila Gingold, Victor Stolzenbach, Sarit Anava, Olga Antonova, Erin J Cram, Oded Rechavi, Ronen Zaidel-Bar.
      Collective cell invasion underlies organ development, epithelial repair, and cancer metastasis. "Leader cells" remodel ECM, sense guidance cues, reorganize their cytoskeleton, and coordinate follower cells, but the molecular programs enabling these functions remain unclear. Here, we present a stage-specific transcriptomic dataset of the Caenorhabditis elegans gonadal leader cell, the distal tip cell (DTC), which invades basement membrane and guides germ cells to form U-shaped gonadal arms. Comparing invasive larval-stage DTCs with noninvasive adult-stage DTCs defines the molecular signature of an actively invading leader cell in vivo. Our dataset recapitulates known regulators of gonad morphogenesis and reveals numerous uncharacterized genes with potential roles in leader cell activity. Demonstrating dataset utility, we identify vesicular trafficking proteins enriched in invading DTCs and demonstrate their importance for gonad development using endogenous tagging and DTC-specific RNAi. We also catalog diverse DTC-specific knockdown phenotypes. This resource establishes a molecular framework for leader cell activity and a platform to investigate conserved mechanisms of invasive migration.
    DOI:  https://doi.org/10.1083/jcb.202509224
  36. Dev Biol. 2026 Mar 17. pii: S0012-1606(26)00070-9. [Epub ahead of print]
    The Dynamic Landscape of Alternative 3' UTR during Mammalian Preimplantation Development.
    Yu Zhang, Anqi Li, Jieyu Wu, Irina A Tuzankina, Shuhua Xu, Yongqiang Xing.
      Alternative polyadenylation (APA) generates mRNA isoforms with distinct 3' UTR lengths, yet its role in mammalian preimplantation development remains largely unexplored. Here, we systematically delineated single-cell 3' UTR APA dynamics in human and mouse preimplantation embryos. The pronounced cell heterogeneity and developmental stage-specific of APA patterns were uncovered. Zygotic genome activation (ZGA) genes predominantly utilized shortened 3' UTRs, indicating a potential role for 3' UTR shortening in ZGA. Integrative analyses with APAFlow and DAPAFlow revealed that N6-methyladenosine modification and its reader proteins coordinately regulate APA via APA-associated factors during ZGA. Moreover, the occurrence and expression of 3' UTR APA events are linked to miRNAs located adjacent to polyadenylation sites. Together, these findings delineate a dynamic 3' UTR APA landscape across mammalian preimplantation stages, highlighting its contribution to cellular heterogeneity and developmental regulation. Shortened 3' UTR APA may serve as a hallmark of ZGA, providing new insight into post-transcriptional regulation during preimplantation development.
    Keywords:  Mammals; alternative polyadenylation; early embryonic development; miRNA; zygotic genome activation
    DOI:  https://doi.org/10.1016/j.ydbio.2026.03.014
  37. Proc Natl Acad Sci U S A. 2026 Mar 24. 123(12): e2519117123
    Phosphorylation and DNA damage resolution coordinate SOX2-mediated reprogramming in vivo.
    Xiaoling Zhong, Yuhua Zou, Chun-Li Zhang.
      The stem cell factor SOX2 can reprogram resident glial cells into neurons in the adult mammalian central nervous system, but the molecular mechanisms underlying this process remain poorly understood. Here, we show that both SOX2 phosphorylation and the PRKDC-dependent nonhomologous end joining (NHEJ) pathway are essential for SOX2-mediated in vivo glia-to-neuron reprogramming. A phospho-mimetic SOX2 mutant significantly enhances reprogramming output without altering neuronal fate. Conversely, loss of PRKDC or knockdown of core NHEJ components KU80 and LIG4 abolishes reprogramming. Notably, p53 knockdown restores reprogramming in PRKDC-deficient mice, likely by overcoming DNA damage-induced cell-cycle arrest. These findings demonstrate that SOX2-driven glial reprogramming requires both precise posttranslational regulation and effective DNA damage repair and suggest that targeting these pathways could enhance regenerative strategies in the CNS.
    Keywords:  NHEJ; PRKDC; SOX2; adult neurogenesis; glia-to-neuron reprogramming
    DOI:  https://doi.org/10.1073/pnas.2519117123
  38. EMBO J. 2026 Mar 19.
    Transcription factor NFYA directs male meiotic entry by regulating accessible chromatin at meiotic promoters in mice.
    Martin Säflund, Masomeh Askari, Atiyeh Eghbali, Mukhtar Mohamed Abdi, Dilay Deren Er, Ann-Kristin Östlund Farrants, Tianxiong Yu, Deniz M Özata.
      Meiotic prophase I, characterized by homologous recombination and synapsis, is a critical step in spermatogenesis. This process entails extensive changes to chromatin and transcription. Prior to prophase I, accessible chromatin bound by paused Pol II at meiotic gene promoters is essential for their timely activation later during meiosis. However, the factors responsible for establishing accessible chromatin at meiotic gene promoters before entry into prophase I are unknown. Here, we discovered that NFYA, expressed in pre-meiotic germ cells, regulates accessible chromatin at meiotic gene promoters, including those activated by the STRA8/MEISON axis. Concordantly, conditional germline deletion of Nfya in male mice blocks meiotic entry. Single-cell ATAC-seq analysis shows that loss of NFYA in pre-meiotic cells disrupts accessible chromatin at poised meiotic gene promoters. These findings establish NFYA as a regulator of accessible chromatin at meiotic gene promoters and of the timely activation of the meiotic genetic program.
    Keywords:  Meiosis; Meiotic Initiation; Single-cell Multi-omics; Spermatogenesis; Transcription Factor NFYA
    DOI:  https://doi.org/10.1038/s44318-026-00756-6
  39. Nat Neurosci. 2026 Mar 19.
    Single-nucleus epigenomic profiling of the adult human central nervous system unveils epigenetic memory of developmental programs.
    Mukund Kabbe, Eneritz Agirre, Karl E Carlström, Özge Dumral, Yuk Kit Lor, Fabio Baldivia Pohl, Nicolas Ruffin, David van Bruggen, Mandy Meijer, Luise A Seeker, Nadine Bestard-Cuche, Alex R Lederer, Jilin Zhang, Virpi Ahola, Steven A Goldman, Erik Edström, Lisa Arvidsson, Tiago Holm Moreira, Marek Bartosovic, Maja Jagodic, Anna Williams, Gonçalo Castelo-Branco.
      Neural cells in the adult human central nervous system (CNS) display extensive transcriptional heterogeneity. How different layers of epigenetic regulation underpin this heterogeneity is poorly understood. Here we profile, at the single-nuclei epigenomic level, distinct regions of the adult human CNS, for chromatin accessibility and simultaneously for the histone modifications H3K27me3 and H3K27ac. We unveil a putative SOX10 enhancer and primed chromatin signatures at HOX loci in spinal-cord-derived human oligodendroglia (OLG) and astrocytes, but not microglia. These signatures in adult OLG were reminiscent of developmental profiles but were decoupled from robust gene expression. Moreover, using high-resolution Micro-C, we show that induced pluripotent stem-cell-derived human OLGs exhibit a HOX chromatin architecture compatible with the primed chromatin in adult OLGs, bearing a strong resemblance not only to OLG developmental architecture but also to high-grade pontine gliomas. Thus, epigenetic memory from developmental states in adult OLG not only enables them to promptly transcribe Hox family genes during regeneration but also makes them susceptible to gliomagenesis.
    DOI:  https://doi.org/10.1038/s41593-026-02208-0
  40. Nature. 2026 Mar 18.
    The E3 ubiquitin ligase mechanism specifying targeted microRNA degradation.
    Jakob Farnung, Elena Slobodyanyuk, Peter Y Wang, Lianne W Blodgett, Daniel H Lin, Susanne von Gronau, Brenda A Schulman, David P Bartel.
      MicroRNAs (miRNAs) associate with Argonaute (AGO) proteins to form complexes that down-regulate target RNAs, including messenger RNAs from most human genes1-3. Within each complex, the miRNA pairs to target RNAs, and AGO provides effector function while also protecting the miRNA from cellular nucleases2-5. Although much is known about miRNA-directed gene regulation, less is known about how miRNAs themselves are regulated. One pathway that regulates miRNAs involves unusual targets called 'trigger' RNAs, which reverse the canonical regulatory logic and instead down-regulate miRNAs6-9. This target-directed miRNA degradation (TDMD) is thought to require a cullin-RING E3 ligase because it depends on the cullin protein CUL3 and other ubiquitylation components, including the BC-box protein ZSWIM8 (refs. 10,11). ZSWIM8 is required for murine perinatal viability and for destabilization of most short-lived miRNAs, which suggests biological importance of TDMD11-13. Here, biochemical and cellular assays establish AGO binding and polyubiquitylation by the ZSWIM8-CUL3 E3 ligase as the key regulatory steps of TDMD, and thereby define a unique cullin-RING E3 ligase class. Cryogenic electron microscopy analyses show ZSWIM8 recognizing distinct AGO and RNA conformations shaped by pairing of the miRNA to the trigger. Specificity of AGO ubiquitylation is established through generalizable RNA-RNA, RNA-protein and protein-protein interactions. The substrate features recognized by the E3 ligase do not conform to a conventional degron14,15 but instead establish a two-RNA-factor authentication mechanism for specifying a protein ubiquitylation substrate.
    DOI:  https://doi.org/10.1038/s41586-026-10232-0
  41. Proc Natl Acad Sci U S A. 2026 Mar 24. 123(12): e2529914123
    SEL1L-HRD1 ERAD-autophagy interplay maintains mitochondrial homeostasis in brown adipocytes.
    Xinxin Chen, Siwen Wang, Mauricio Torres, Sijie Hao, Shengyi Sun, Ling Qi.
      Mitochondrial integrity is central to energy homeostasis, particularly in brown adipose tissue where dynamic remodeling fuels thermogenesis. Two major proteostatic systems, the SEL1L-HRD1 endoplasmic reticulum (ER)-associated degradation (ERAD) pathway and autophagy, have been shown to intersect in vitro, but their physiological coordination in metabolically active tissues remains unclear. Here, we demonstrate that ERAD and autophagy act in synergy to safeguard mitochondrial integrity in brown adipocytes. Using various adipocyte-specific knockout (KO) mouse models and high-resolution ultrastructural 2D and 3D imaging, we show that simultaneous deletion of Sel1L and Atg7 (double KO, DKO) causes striking mitochondrial abnormalities under room temperature, absent in single KO or Sel1L-Ire1a double knockout mice. DKO adipocytes accumulate hyperfused megamitochondria extensively penetrated by ER tubules, accompanied by ER expansion, excessive ER-mitochondrial contacts, and impaired thermogenesis. These findings reveal that SEL1L-HRD1 ERAD and autophagy cooperate, rather than act redundantly, to maintain mitochondrial integrity in brown fat, uncovering a previously unrecognized mitochondrial surveillance mechanism based on ERAD-autophagy crosstalk.
    Keywords:  3D FIB-SEM; ER–mitochondrial contacts; brown adipocytes; megamitochondria; thermogenesis
    DOI:  https://doi.org/10.1073/pnas.2529914123
  42. Curr Opin Genet Dev. 2026 Mar 18. pii: S0959-437X(26)00030-4. [Epub ahead of print]98 102463
    Mechanisms of lung regeneration and repair.
    Ashutosh Tripathy, Gamze Cigdem Gelincik, Ana Pardo-Saganta.
      The adult lung maintains tissue integrity through adaptable regenerative programs that rely on the plasticity of epithelial progenitor cells across airway and alveolar compartments. Rather than following a linear stem-cell hierarchy, regeneration is driven by context-dependent lineage behaviors shaped by local signaling pathways, metabolic state, epigenetic regulation, and biophysical cues. Basal cells are the main stem cells of the airway epithelium, whereas alveolar type 2 cells act as the stem cells in the alveoli and regenerate the gas-exchange surface through defined transitional states. These processes are regulated by main signaling networks, including Wnt/β-catenin, Notch, fibroblast growth factor, bone morphogenetic protein / SMAD family proteins, and Hippo-Yes-assciated protein / transcriptional co-activator with PDZ-binding motif, which integrate niche-derived signals and mechanical inputs to control stem/progenitor activation and fate decisions. Disruption or persistence of these signaling networks leads to inefficient or aberrant repair and contributes to chronic lung disease. This review summarizes recent findings in cellular and molecular mechanisms of lung regeneration and highlights how controlled epithelial plasticity determines the balance between effective repair and disease-associated outcomes.
    DOI:  https://doi.org/10.1016/j.gde.2026.102463
  43. Trends Genet. 2026 Mar 19. pii: S0168-9525(26)00057-0. [Epub ahead of print]
    Replication origin flexibility: a tool to mitigate the hazards of excess replication.
    Haiqing Fu, Christophe E Redon, Hannah M Brenner, Michael R Ack, Mirit I Aladjem.
      Chromosome duplication is critical for genome integrity, yet inaccurate DNA synthesis can induce DNA damage and foster structural genomic variations. Cells mitigate these risks using flexible replication initiation mechanisms responsive to changes in chromatin structure, transcriptional cues, and nuclear architecture. Recent studies reveal chromatin-dependent mechanisms preventing DNA synthesis at damaged nuclear compartments while permitting replication elsewhere. To minimize replication stress, cells activate signaling cascades with dual roles: blocking replication at dormant origins to prevent over-replication during normal growth and activating dormant origins when replication is perturbed to ensure genome integrity. Here, we explore molecular pathways governing selective origin activation in response to replication stress and DNA damage. Understanding these pathways could reveal therapeutic vulnerabilities in cancer cells' altered replication landscapes.
    DOI:  https://doi.org/10.1016/j.tig.2026.02.005
  44. Cell Chem Biol. 2026 Mar 17. pii: S2451-9456(26)00064-4. [Epub ahead of print]
    Control of the signaling of RAS proteins by modulating their palmitoylation.
    Jiakai Zhu, Ruiying Guo, Qi Hu.
      Small GTPases are key regulators of cell proliferation and oncogenesis. S-palmitoylation catalyzed by ZDHHC enzymes regulates many small GTPases, such as RAS family proteins, by modulating their subcellular localization. The development of chemical tools to modulate S-palmitoylation remains challenging due to the redundancy and poor druggability of ZDHHC enzymes. Here, we developed an approach to modulate RAS palmitoylation by fusing a depalmitoylase, acyl-protein thioesterase 1 (APT1), to the N-terminus of RAS proteins. S-palmitoylation, and thus the subcellular localization of RAS in the fusion proteins, can be reversibly controlled by an APT1 inhibitor, ML348. Using this approach, we developed a cell-based high-throughput assay to screen small-molecule regulators of NRAS palmitoylation and identified six compounds that inhibit the ZDHHC9-GCP16 complex, which catalyzes RAS palmitoylation, with IC50 values ranging from 1.4 to 8.0 μM. Thus, our approach provides a useful tool for studying S-palmitoylation and screening regulators of this important post-translational modification.
    Keywords:  APT1; GCP16; HRAS; KRAS4a; NRAS; RAS; S-acylation; ZDHHC9; depalmitoylation; palmitoylation
    DOI:  https://doi.org/10.1016/j.chembiol.2026.02.009
  45. Neuron. 2026 Mar 13. pii: S0896-6273(26)00055-3. [Epub ahead of print]
    A genetically encoded fluorescent sensor for monitoring spatiotemporal prostaglandin E2 dynamics in vivo.
    Lei Wang, Yini Yang, Fei Deng, Yuqi Yan, Huan Wang, Bohan Li, Jinxia Wan, Yulong Li.
      Prostaglandin E2 (PGE2) is an important lipid signaling molecule that regulates a wide range of physiological and pathological processes. However, its dynamics during these processes are largely unknown due to the lack of tools to directly visualize PGE2 with high spatiotemporal resolution. Here, we developed and characterized a genetically encoded G-protein-coupled receptor (GPCR) activation-based (GRAB) PGE2 sensor, which we call GRABPGE2-1.0 (PGE2-1.0), that has high specificity for PGE2, nanomolar affinity, rapid kinetics, and high spatial resolution when expressed both in vitro and in vivo. Using fiber-photometry recordings, we found that PGE2-1.0 can reliably monitor endogenous PGE2 dynamics in the preoptic area in the brain during acute inflammation. Wide-field in vivo imaging with PGE2-1.0 reveals spatial heterogeneity in cortex-wide PGE2 dynamics during acute inflammation and seizure. Thus, our PGE2-1.0 sensor can be used to detect endogenous PGE2 dynamics with high spatiotemporal resolution, providing a robust tool for studying PGE2 under specific physiological and pathological conditions.
    Keywords:  GRAB; fluorescent sensor; inflammation; prostaglandin; prostaglandin E2; seizure
    DOI:  https://doi.org/10.1016/j.neuron.2026.01.030
  46. Nature. 2026 Mar 18.
    Synthetic circuits for cell ratio control.
    Bolin An, Tzu-Chieh Tang, Qian Zhang, Teng Wang, Yanyi Wang, Kesheng Gan, Kun Liu, Daniel L Zhang, Yuzhu Liu, Yu Kui Pan, Min Yu, William M Shaw, Qianyi Liang, Yaomin Wang, Christopher A Vaiana, Chunbo Lou, Christopher A Voigt, Timothy K Lu, George M Church, Chao Zhong.
      Recent advances in genetic engineering have provided diverse tools for artificially diversifying both prokaryotic and eukaryotic cell populations1-6. However, achieving precise control over the ratios of multiple cell types within a population derived from a single founder remains a major challenge. Here we introduce a suite of recombinase-mediated genetic devices designed to accurately control population ratios, enabling the distribution of distinct functionalities across multiple cell types. We systematically evaluated key parameters that influence recombination efficiency and developed data-driven models to reliably predict binary differentiation outcomes. Using these devices, we constructed parallel and series circuit topologies to implement user-defined, multistep cell-fate branching programs. The branching devices facilitated the autonomous differentiation of precision fermentation consortia from a single founder yeast strain, optimizing cell-type ratios for applications such as pigmentation and cellulose degradation. Similar effects were obtained with mammalian cells. We also engineered multicellular aggregates with genetically encoded morphologies by coordinating self-organization through cell adhesion molecules. Our work provides a comprehensive characterization of recombinase-based cell-fate branching mechanisms and introduces an approach for constructing synthetic consortia and multicellular assemblies.
    DOI:  https://doi.org/10.1038/s41586-026-10259-3
  47. Circ Res. 2026 Mar 20.
    ESCRT-Mediated Machinery Directly Drives Cardiac T-Tubule Formation.
    Xinjian Wang, Shuxian Han, Ge Zhang, Xiaozhi Huang, Chen Xu, Jiayin Zhang, Yuyuan Zheng, Pengwei Zhao, Tao Lin, Zijian Feng, Duane D Hall, Qiming Sun, Chun Zhou, Hong-Kun Wu, Long-Sheng Song, Peidong Han.
       BACKGROUND: Transverse tubules (T-tubules) are invaginations of the plasma membrane crucial for excitation-contraction coupling. Disruptions in T-tubule organization are frequently observed in heart diseases and are associated with impaired contractile function and malignant arrhythmias. In mammalian cells, the ESCRT (endosomal sorting complex required for transport) proteins mediate a fundamental mechanism for membrane deformation. This study aimed to elucidate the roles of key ESCRT proteins, including Chmp (charged multivesicular body protein) 4b and Tsg101 (tumor susceptibility gene 101), in the formation and maintenance of T-tubules.
    METHODS: Myocardial-specific gene deletion was achieved using Chmp4bF/F, Tsg101F/F, and Rosa26Cas9-GFP mouse strains in conjunction with adeno-associated virus 9-mediated gene editing. The polymerization state of Chmp4b was assessed through the introduction of point mutations combined with glycerol-gradient fractionation. Direct interaction between Chmp4b and membrane phospholipids was examined using genetically encoded biosensors, lipid strip binding, and liposome tubulation assays. An inducible Chmp4b knockout model was utilized to determine its role in T-tubule maintenance during adulthood. Chmp4b expression levels were analyzed in a heart failure mouse model and in human patients with dilated cardiomyopathy.
    RESULTS: Chmp4b gradually localizes to the dyad during postnatal development, with its deletion causing a complete loss of T-tubules and defects in cardiac structure and contractile function. Chmp4b polymerizes and binds to PtdIns(4,5)P2 as well as other negatively charged membrane lipids, driving plasma membrane invagination in a process that depends on the ESCRT-I component Tsg101. In mature cardiomyocytes, Chmp4b remains anchored to the T-tubule membranes to maintain their structure, while Tsg101 detaches and becomes dispensable for T-tubule organization. Chmp4b expression was significantly reduced in heart samples from dilated cardiomyopathy patients and in a mouse model of heart failure.
    CONCLUSIONS: These results uncover an ESCRT-mediated membrane deformation machinery that is essential for shaping cardiomyocyte structure in physiological and disease conditions.
    Keywords:  cardiomyopathy, dilated; cell membrane; endosomal sorting complex required for transport; heart; myocytes, cardiac
    DOI:  https://doi.org/10.1161/CIRCRESAHA.125.327453
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