bims-ginsta Biomed News
on Genome instability
Issue of 2025–04–27
23 papers selected by
Jinrong Hu, National University of Singapore
  1. Border-zone cardiomyocytes and macrophages regulate extracellular matrix remodeling to promote cardiomyocyte protrusion during cardiac regeneration.
  2. RIF1 controls replication timing in early mouse embryos independently of lamina-associated nuclear organization.
  3. α-Ketoglutarate promotes trophectoderm induction and maturation from naive human embryonic stem cells.
  4. The establishment of nuclear organization in mouse embryos is orchestrated by multiple epigenetic pathways.
  5. Frictiotaxis underlies focal adhesion-independent durotaxis.
  6. Engineered epithelial curvature controls Paneth cell localization in intestinal organoids.
  7. An organ-wide spatiotemporal transcriptomic and cellular atlas of the regenerating zebrafish heart.
  8. Dual states of murine Bmi1-expressing intestinal stem cells drive epithelial development utilizing non-canonical Wnt signaling.
  9. Transcriptional regulation by PHGDH drives amyloid pathology in Alzheimer's disease.
  10. The retrotransposon-derived capsid genes PNMA1 and PNMA4 maintain reproductive capacity.
  11. Treatment of acute myeloid leukemia models by targeting a cell surface RNA-binding protein.
  12. The adult ovary at single cell resolution: an expert review.
  13. SGO2 does not play an essential role in separase inhibition during meiosis I in mouse oocytes.
  14. Three-dimensional genome structures of single mammalian sperm.
  15. Pooled tagging and hydrophobic targeting of endogenous proteins for unbiased mapping of unfolded protein responses.
  16. Phosphorylation modulates secondary structure of intrinsically disorder regions in RNA polymerase II.
  17. BMAL1-HIF2A heterodimer modulates circadian variations of myocardial injury.
  18. PI3K/AKT signaling mediates stress-inducible amyloid formation through c-Myc.
  19. Epithelial cell extrusion at a glance.
  20. Protein O-GlcNAcylation and hexokinase mitochondrial dissociation drive heart failure with preserved ejection fraction.
  21. Effects of embryonic origin, tissue cues and pathological signals on fibroblast diversity in humans.
  22. Distinct adipose progenitor cells emerging with age drive active adipogenesis.
  23. Deciphering disordered regions controlling mRNA decay in high-throughput.
  1. Nat Commun. 2025 Apr 23. 16(1): 3823
    Border-zone cardiomyocytes and macrophages regulate extracellular matrix remodeling to promote cardiomyocyte protrusion during cardiac regeneration.
    Florian Constanty, Bailin Wu, Ke-Hsuan Wei, I-Ting Lin, Julia Dallmann, Stefan Guenther, Till Lautenschlaeger, Rashmi Priya, Shih-Lei Lai, Didier Y R Stainier, Arica Beisaw.
      Despite numerous advances in our understanding of zebrafish cardiac regeneration, an aspect that remains less studied is how regenerating cardiomyocytes invade and replace the collagen-containing injured tissue. Here, we provide an in-depth analysis of the process of cardiomyocyte invasion. We observe close interactions between protruding border-zone cardiomyocytes and macrophages, and show that macrophages are essential for extracellular matrix remodeling at the wound border zone and cardiomyocyte protrusion into the injured area. Single-cell RNA-sequencing reveals the expression of mmp14b, encoding a membrane-anchored matrix metalloproteinase, in several cell types at the border zone. Genetic mmp14b mutation leads to decreased macrophage recruitment, collagen degradation, and subsequent cardiomyocyte protrusion into injured tissue. Furthermore, cardiomyocyte-specific overexpression of mmp14b is sufficient to enhance cardiomyocyte invasion into the injured tissue and along the apical surface of the wound. Altogether, our data provide important insights into the mechanisms underlying cardiomyocyte invasion of the collagen-containing injured tissue during cardiac regeneration.
    DOI:  https://doi.org/10.1038/s41467-025-59169-4
  2. Dev Cell. 2025 Apr 16. pii: S1534-5807(25)00179-0. [Epub ahead of print]
    RIF1 controls replication timing in early mouse embryos independently of lamina-associated nuclear organization.
    Tsunetoshi Nakatani, Tamas Schauer, Mrinmoy Pal, Andreas Ettinger, Luis Altamirano-Pacheco, Julia Zorn, David M Gilbert, Maria-Elena Torres-Padilla.
      Cells must duplicate their genome before they divide to ensure equal transmission of genetic information. The genome is replicated with a defined temporal order, replication timing (RT), which is cell-type specific and linked to 3D-genome organization. During mammalian development, RT is initially not well defined and becomes progressively consolidated from the 4-cell stage. However, the molecular regulators are unknown. Here, by combining loss-of-function analysis with genome-wide investigation of RT in mouse embryos, we identify Rap1 interacting factor 1 (RIF1) as a regulator of the progressive consolidation of RT. Embryos without RIF1 show DNA replication features of an early, more totipotent state. RIF1 regulates the progressive stratification of RT values and its depletion leads to global RT changes and a more heterogeneous RT program. Developmental RT changes are disentangled from changes in transcription and nuclear organization, specifically nuclear lamina association. Our work provides molecular understanding of replication and genome organization at the beginning of mammalian development.
    Keywords:  RIF1; early mouse embryos; lamina-associated domains; replication fork speed; replication timing; single-cell Repli-seq
    DOI:  https://doi.org/10.1016/j.devcel.2025.03.016
  3. Nat Cell Biol. 2025 Apr 23.
    α-Ketoglutarate promotes trophectoderm induction and maturation from naive human embryonic stem cells.
    Karlien Van Nerum, Anne Wenzel, Lidia Argemi-Muntadas, Eleni Kafkia, Antar Drews, Ida Sophie Brun, Viktoria Lavro, Annina Roelofsen, Nikolaos Stamidis, Sandra Bages Arnal, Cheng Zhao, Simone di Sanzo, Moritz Völker-Albert, Sophie Petropoulos, Thomas Moritz, Jan Jakub Żylicz.
      Development and lineage choice are driven by interconnected transcriptional, epigenetic and metabolic changes. Specific metabolites, such as α-ketoglutarate (αKG), function as signalling molecules affecting the activity of chromatin-modifying enzymes. However, how metabolism coordinates cell-state changes, especially in human pre-implantation development, remains unclear. Here we uncover that inducing naive human embryonic stem cells towards the trophectoderm lineage results in considerable metabolic rewiring, characterized by αKG accumulation. Elevated αKG levels potentiate the capacity of naive embryonic stem cells to specify towards the trophectoderm lineage. Moreover, increased αKG levels promote blastoid polarization and trophectoderm maturation. αKG supplementation does not affect global histone methylation levels; rather, it decreases acetyl-CoA availability, reduces histone acetyltransferase activity and weakens the pluripotency network. We propose that metabolism functions as a positive feedback loop aiding in trophectoderm fate induction and maturation, highlighting that global metabolic rewiring can promote specificity in cell fate decisions through intricate regulation of signalling and chromatin.
    DOI:  https://doi.org/10.1038/s41556-025-01658-1
  4. Cell. 2025 Apr 15. pii: S0092-8674(25)00396-4. [Epub ahead of print]
    The establishment of nuclear organization in mouse embryos is orchestrated by multiple epigenetic pathways.
    Mrinmoy Pal, Tamas Schauer, Adam Burton, Tsunetoshi Nakatani, Federico Pecori, Alicia Hernández-Giménez, Iliya Nadelson, Marc A Marti-Renom, Maria-Elena Torres-Padilla.
      The folding of the genome in the 3D nuclear space is fundamental for regulating all DNA-related processes. The association of the genome with the nuclear lamina into lamina-associated domains (LADs) represents the earliest feature of nuclear organization during development. Here, we performed a gain-of-function screen in mouse embryos to obtain mechanistic insights. We find that perturbations impacting histone H3 modifications, heterochromatin, and histone content are crucial for the establishment of nuclear architecture in zygotes and/or 2-cell-stage embryos. Notably, some perturbations exerted differential effects on zygotes versus 2-cell-stage embryos. Moreover, embryos with disrupted LADs can rebuild nuclear architecture at the 2-cell stage, indicating that the initial establishment of LADs in zygotes might be dispensable for early development. Our findings provide valuable insights into the functional interplay between chromatin and structural components of the nucleus that guide genome-lamina interactions during the earliest developmental stages.
    Keywords:  3D genome organization; LAD; MZT; ZGA; epigenetics; mouse embryo; nuclear architecture
    DOI:  https://doi.org/10.1016/j.cell.2025.03.044
  5. Nat Commun. 2025 Apr 23. 16(1): 3811
    Frictiotaxis underlies focal adhesion-independent durotaxis.
    Adam Shellard, Kai Weißenbruch, Peter A E Hampshire, Namid R Stillman, Christina L Dix, Richard Thorogate, Albane Imbert, Guillaume Charras, Ricard Alert, Roberto Mayor.
      Cells move directionally along gradients of substrate stiffness - a process called durotaxis. In the situations studied so far, durotaxis relies on cell-substrate focal adhesions to sense stiffness and transmit forces that drive directed motion. However, whether and how durotaxis can take place in the absence of focal adhesions remains unclear. Here, we show that confined cells can perform durotaxis despite lacking focal adhesions. This durotactic migration depends on an asymmetric myosin distribution and actomyosin retrograde flow. We propose that the mechanism of this focal adhesion-independent durotaxis is that stiffer substrates offer higher friction. We put forward a physical model that predicts that non-adherent cells polarise and migrate towards regions of higher friction - a process that we call frictiotaxis. We demonstrate frictiotaxis in experiments by showing that cells migrate up a friction gradient even when stiffness is uniform. Our results broaden the potential of durotaxis to guide any cell that contacts a substrate, and they reveal a mode of directed migration based on friction. These findings have implications for cell migration during development, immune response and cancer progression, which usually takes place in confined environments that favour adhesion-independent amoeboid migration.
    DOI:  https://doi.org/10.1038/s41467-025-58912-1
  6. Cell Biomater. 2025 Apr 22. pii: 100046. [Epub ahead of print]1(3):
    Engineered epithelial curvature controls Paneth cell localization in intestinal organoids.
    F Max Yavitt, Alex Khang, Kaustav Bera, Delaney L McNally, Michael R Blatchley, Aaron P Gallagher, Ophir D Klein, David Castillo-Azofeifa, Peter J Dempsey, Kristi S Anseth.
      The cellular organization within organoid models is important to regulate tissue specific function, yet few engineering approaches can control or direct cellular organization. Here, a photodegradable hydrogel is used to create softened regions that direct crypt formation within intestinal organoids, where the dimensions of the photosoftened regions generate predictable and defined crypt architectures. Guided by in vivo metrics of crypt morphology, this photopatterning method is used to control the width and length of in vitro organoid crypts, which ultimately defines the curvature of the epithelium. By tracking expression of differentiated Paneth cell markers in real-time, we show that epithelial curvature directs the localization of Paneth cells within engineered crypts, providing user-directed control over organoid functionality. We anticipate that our improved control over organoid architecture and thus Paneth cell localization will lead to more consistent in vitro organoid models for both mechanistic studies and translational applications.
    DOI:  https://doi.org/10.1016/j.celbio.2025.100046
  7. Nat Commun. 2025 Apr 19. 16(1): 3716
    An organ-wide spatiotemporal transcriptomic and cellular atlas of the regenerating zebrafish heart.
    Lei Li, Meina Lu, Lidong Guo, Xuejiao Zhang, Qun Liu, Meiling Zhang, Junying Gao, Mengyang Xu, Yijian Lu, Fang Zhang, Yao Li, Ruihua Zhang, Xiawei Liu, Shanshan Pan, Xianghui Zhang, Zhen Li, Yadong Chen, Xiaoshan Su, Nannan Zhang, Wenjie Guo, Tao Yang, Jing Chen, Yating Qin, Zhe Zhang, Wei Cui, Lindong Yu, Ying Gu, Huanming Yang, Xun Xu, Jianxun Wang, Caroline E Burns, C Geoffrey Burns, Kai Han, Long Zhao, Guangyi Fan, Ying Su.
      Adult zebrafish robustly regenerate injured hearts through a complex orchestration of molecular and cellular activities. However, this remarkable process, which is largely non-existent in humans, remains incompletely understood. Here, we utilize integrated spatial transcriptomics (Stereo-seq) and single-cell RNA-sequencing (scRNA-seq) to generate a spatially-resolved molecular and cellular atlas of regenerating zebrafish heart across eight stages. We characterize the cascade of cardiomyocyte cell states responsible for producing regenerated myocardium and explore a potential role for tpm4a in cardiomyocyte re-differentiation. Moreover, we uncover the activation of ifrd1 and atp6ap2 genes as a unique feature of regenerative hearts. Lastly, we reconstruct a 4D "virtual regenerating heart" comprising 569,896 cells/spots derived from 36 scRNA-seq libraries and 224 Stereo-seq slices. Our comprehensive atlas serves as a valuable resource to the cardiovascular and regeneration scientific communities and their ongoing efforts to understand the molecular and cellular mechanisms underlying vertebrate heart regeneration.
    DOI:  https://doi.org/10.1038/s41467-025-59070-0
  8. Dev Cell. 2025 Apr 16. pii: S1534-5807(25)00177-7. [Epub ahead of print]
    Dual states of murine Bmi1-expressing intestinal stem cells drive epithelial development utilizing non-canonical Wnt signaling.
    Nicholas R Smith, Nicole R Giske, Sidharth K Sengupta, Patrick Conley, John R Swain, Ashvin Nair, Kathryn L Fowler, Christopher Klocke, Yeon Jung Yoo, Ashley N Anderson, Nasim Sanati, Kristof Torkenczy, Andrew C Adey, Jared M Fischer, Guanming Wu, Melissa H Wong.
      Intestinal epithelial development and homeostasis critically rely upon balanced stem cell proliferation, involving slow-cycling/label-retaining and active-cycling/canonical Wnt-dependent intestinal stem cell (ISC) subtypes. ISC regulation during development remains poorly understood but has important implications for establishing key mechanisms governing tissue maintenance. Herein, we identify Bmi1+ cells as functional stem cells present in early murine intestinal development, prior to Lgr5-expressing ISCs. Lineage tracing and single-cell RNA sequencing identify that Bmi1+ ISCs can trace to Lgr5+ ISCs and other differentiated lineages. Initially highly proliferative, Bmi1+ ISCs transition to slow-cycling states as Lgr5+ ISCs emerge. Non-canonical Wnt signaling regulates the proliferative Bmi1+ cell state. These findings highlight the dynamic interplay between stem cell populations and the opposing Wnt pathways that govern proliferation-ultimately having implications for tissue development, homeostasis, regeneration, and tumorigenesis. Understanding these fundamental developmental mechanisms is critical for understanding adult intestinal maintenance.
    Keywords:  Bmi1; Wnt signaling; development; intestinal stem cell
    DOI:  https://doi.org/10.1016/j.devcel.2025.03.014
  9. Cell. 2025 Apr 17. pii: S0092-8674(25)00397-6. [Epub ahead of print]
    Transcriptional regulation by PHGDH drives amyloid pathology in Alzheimer's disease.
    Junchen Chen, Fatemeh Hadi, Xingzhao Wen, Wenxin Zhao, Ming Xu, Shuanghong Xue, Pei Lin, Riccardo Calandrelli, John Lalith Charles Richard, Zhixuan Song, Jessica Li, Alborz Amani, Yang Liu, Xu Chen, Sheng Zhong.
      Virtually all individuals aged 65 or older develop at least early pathology of Alzheimer's disease (AD), yet most lack disease-causing mutations in APP, PSEN, or MAPT, and many do not carry the APOE4 risk allele. This raises questions about AD development in the general population. Although transcriptional dysregulation has not traditionally been a hallmark of AD, recent studies reveal significant epigenomic changes in late-onset AD (LOAD) patients. We show that altered expression of the LOAD biomarker phosphoglycerate dehydrogenase (PHGDH) modulates AD pathology in mice and human brain organoids independent of its enzymatic activity. PHGDH has an uncharacterized role in transcriptional regulation, promoting the transcription of inhibitor of nuclear factor kappa-B kinase subunit alpha (IKKa) and high-mobility group box 1 (HMGB1) in astrocytes, which suppress autophagy and accelerate amyloid pathology. A blood-brain-barrier-permeable small-molecule inhibitor targeting PHGDH's transcriptional function reduces amyloid pathology and improves AD-related behavioral deficits. These findings highlight transcriptional regulation in LOAD and suggest therapeutic strategies beyond targeting familial mutations.
    Keywords:  Alzheimer’s disease; LOAD; PHGDH; amyloid pathology; astrocyte; biomarker; small molecule; therapeutic candidate; transcriptional regulation
    DOI:  https://doi.org/10.1016/j.cell.2025.03.045
  10. Nat Aging. 2025 Apr 22.
    The retrotransposon-derived capsid genes PNMA1 and PNMA4 maintain reproductive capacity.
    Thomas W P Wood, William S Henriques, Harrison B Cullen, Mayra Romero, Cecilia S Blengini, Shreya Sarathy, Julia Sorkin, Hilina Bekele, Chen Jin, Seungsoo Kim, Xifan Wang, Raphaelle Laureau, Alexei Chemiakine, Rishad C Khondker, José V V Isola, Michael B Stout, Vincenzo A Gennarino, Binyam Mogessie, Devanshi Jain, Karen Schindler, Yousin Suh, Blake Wiedenheft, Luke E Berchowitz.
      Almost half of the human genome consists of retrotransposons-'parasitic' sequences that insert themselves into the host genome via an RNA intermediate. Although most of these sequences are silenced or mutationally deactivated, they can present opportunities for evolutionary innovation: mutation of a deteriorating retrotransposon can result in a gene that provides a selective advantage to the host in a process termed 'domestication'1-3. The PNMA family of gag-like capsid genes was domesticated from an ancient vertebrate retrotransposon of the Metaviridae clade at least 100 million years ago4,5. PNMA1 and PNMA4 are positively regulated by the master germ cell transcription factors MYBL1 and STRA8, and their transcripts are bound by the translational regulator DAZL during gametogenesis6. This developmental regulation of PNMA1 and PNMA4 expression in gonadal tissue suggested to us that they might serve a reproductive function. Through the analysis of donated human ovaries, genome-wide association studies (GWASs) and mouse models, we found that PNMA1 and PNMA4 are necessary for the maintenance of a normal reproductive lifespan. These proteins self-assemble into capsid-like structures that exit human cells, and we observed large PNMA4 particles in mouse male gonadal tissue that contain RNA and are consistent with capsid formation.
    DOI:  https://doi.org/10.1038/s43587-025-00852-y
  11. Nat Biotechnol. 2025 Apr 23.
    Treatment of acute myeloid leukemia models by targeting a cell surface RNA-binding protein.
    Benson M George, Maria Eleftheriou, Eliza Yankova, Jonathan Perr, Peiyuan Chai, Gianluca Nestola, Karim Almahayni, Siân Evans, Aristi Damaskou, Helena Hemberger, Charlotta G Lebedenko, Justyna Rak, Qi Yu, Ece Bapcum, James Russell, Jaana Bagri, Regan F Volk, Malte Spiekermann, Richard M Stone, George Giotopoulos, Brian J P Huntly, Joanna Baxter, Fernando Camargo, Jie Liu, Balyn W Zaro, George S Vassiliou, Leonhard Möckl, Jorge de la Rosa, Ryan A Flynn, Konstantinos Tzelepis.
      Immunotherapies for acute myeloid leukemia (AML) and other cancers are limited by a lack of tumor-specific targets. Here we discover that RNA-binding proteins and glycosylated RNAs (glycoRNAs) form precisely organized nanodomains on cancer cell surfaces. We characterize nucleophosmin (NPM1) as an abundant cell surface protein (csNPM1) on a variety of tumor types. With a focus on AML, we observe csNPM1 on blasts and leukemic stem cells but not on normal hematopoietic stem cells. We develop a monoclonal antibody to target csNPM1, which exhibits robust anti-tumor activity in multiple syngeneic and xenograft models of AML, including patient-derived xenografts, without observable toxicity. We find that csNPM1 is expressed in a mutation-agnostic manner on primary AML cells and may therefore offer a general strategy for detecting and treating AML. Surface profiling and in vivo work also demonstrate csNPM1 as a target on solid tumors. Our data suggest that csNPM1 and its neighboring glycoRNA-cell surface RNA-binding protein (csRBP) clusters may serve as an alternative antigen class for therapeutic targeting or cell identification.
    DOI:  https://doi.org/10.1038/s41587-025-02648-2
  12. Am J Obstet Gynecol. 2025 Apr;pii: S0002-9378(24)00650-1. [Epub ahead of print]232(4S): S95.e1-S95.e16
    The adult ovary at single cell resolution: an expert review.
    Ilmatar Rooda, Loren Méar, Jasmin Hassan, Pauliina Damdimopoulou.
      The ovaries play a crucial role in both the endocrine health and fertility of adult women. The fundamental functional units of the ovaries, primordial follicles, form during fetal development and constitute the ovarian reserve. Ovaries age prematurely in comparison to other organs, with the quality of oocytes declining steeply prior to the entire reserve becoming depleted, usually around age 50. Despite the pivotal role of ovaries in women's overall health, surprisingly little is known about the mechanisms controlling follicle dormancy, growth activation, atresia, maturation, and oocyte quality. Understanding ovarian function on a cellular and molecular level is increasingly important for several reasons. First, the global trend of women delaying childbirth creates a growing population of patients wishing to conceive when the quality and quantity of their oocytes are already critically low. Second, conditions affecting the ovaries, such as polycystic ovary syndrome and endometriosis, are widespread, yet diagnosis and treatment still present challenges. Lastly, advancements in cancer therapies have increased the number of cancer survivors who contend with late complications affecting fertility and hormonal balance. Clearly, a better understanding of diseases, aging, and toxicity in ovaries is needed for the development of novel treatments, preventive therapies, and safer pharmaceuticals. Human ovaries are notoriously difficult to obtain for research due to their pivotal role in women's health, and the highly heterogeneous distribution of follicles within the tissue combined with monthly cyclical changes present further challenges. Single-cell profiling techniques are creating new opportunities, enabling the characterization of small amounts of tissue with unprecedented resolution. Here, we review the literature on single-cell characterization of adult, reproductive-age ovaries. The majority of the 46 identified studies have focused on oocytes discarded during assisted reproduction, with only a handful focusing on ovarian tissue. The overwhelming focus of the studies is on follicles and oocytes, although the somatic cell niche in the ovary undoubtedly plays an important role in endocrine function and follicle biology. Altogether, the studies reveal unexpected diversity and heterogeneity among ovarian somatic and germ cells, highlighting the prevailing knowledge gaps in basic ovarian biology. As the most common outcome for a follicle is atresia, it is possible that part of the cell diversity relates to the biology of follicles destined to degenerate. The absence of spatial coordinates in single-cell studies further complicates the interpretation of the roles and significance of the various reported cell clusters. Accomplishing a representative ovarian single-cell atlas will require merging these studies. However, direct comparisons are challenging due to nonuniform nomenclature, differing tissue sources, varying meta-data reporting, and lack of gold standards in technical approaches. Although these reports establish a single-cell draft of adult-fertile age human ovaries, more detailed metadata and better quality reporting will be essential for the development of a robust ovarian cell atlas in health and disease.
    Keywords:  RNA-sequencing; epigenetics; fertility; oocyte; ovarian follicle; ovary; proteomics; reproduction; single-cell
    DOI:  https://doi.org/10.1016/j.ajog.2024.05.046
  13. PLoS Biol. 2025 Apr;23(4): e3003131
    SGO2 does not play an essential role in separase inhibition during meiosis I in mouse oocytes.
    Benjamin Wetherall, David Bulmer, Alexandra Sarginson, Christopher Thomas, Suzanne Madgwick.
      During meiosis I in oocytes, anaphase is triggered by deactivation of cyclin B1-CDK1 and activation of separase. Active separase plays an essential role in cleaving cohesin rings that hold homologous chromosomes together. Critically, separase must be inhibited until all chromosomes are aligned and the cell is prepared for anaphase I. Inhibition can be mediated through the binding of separase to either securin or cyclin B1-CDK1. The relative contribution of each inhibitory pathway varies depending on cell type. Recently, shugoshin-2 (SGO2) has also been shown to inhibit separase in mitotic cells. Here, we used a separase biosensor and perturbed the three inhibitory pathways during meiosis I in mouse oocytes. We show that inhibition mediated by either securin or cyclin B1-CDK1, but not SGO2, is independently sufficient to suppress separase activity. However, when both the securin and cyclin B1-CDK1 inhibitory pathways are perturbed together, separase activity begins prematurely, resulting in gross segregation defects. Furthermore, we characterized SGO2 destruction dynamics and concluded that it is not an essential separase inhibitor in mouse oocytes. The existence of multiple separase inhibitory pathways highlights the critical importance of tightly regulated separase activity during this unique and challenging cell division.
    DOI:  https://doi.org/10.1371/journal.pbio.3003131
  14. Nat Commun. 2025 Apr 23. 16(1): 3805
    Three-dimensional genome structures of single mammalian sperm.
    Heming Xu, Yi Chi, Changjian Yin, Cheng Li, Yujie Chen, Zhiyuan Liu, Xiaowen Liu, Hao Xie, Zi-Jiang Chen, Han Zhao, Keliang Wu, Shigang Zhao, Dong Xing.
      The three-dimensional (3D) organization of chromosomes is crucial for packaging a large mammalian genome into a confined nucleus and ensuring proper nuclear functions in somatic cells. However, the packaging of the much more condensed sperm genome is challenging to study with traditional imaging or sequencing approaches. In this study, we develop an enhanced chromosome conformation capture assay, and resolve the 3D whole-genome structures of single mammalian sperm. The reconstructed genome structures accurately delineate the species-specific nuclear morphologies for both human and mouse sperm. We discover that sperm genomes are divided into chromosomal territories and A/B compartments, similarly to somatic cells. However, neither human nor mouse sperm chromosomes contain topologically associating domains or chromatin loops. These results suggest that the fine-scale chromosomal organization of mammalian sperm fundamentally differs from that of somatic cells. The discoveries and methods established in this work will be valuable for future studies of sperm related infertility.
    DOI:  https://doi.org/10.1038/s41467-025-59055-z
  15. Mol Cell. 2025 Apr 18. pii: S1097-2765(25)00305-3. [Epub ahead of print]
    Pooled tagging and hydrophobic targeting of endogenous proteins for unbiased mapping of unfolded protein responses.
    Stephanie E Sansbury, Yevgeniy V Serebrenik, Tomer Lapidot, David G Smith, George M Burslem, Ophir Shalem.
      To achieve system-level insights into proteome organization, regulation, and function, we developed an approach to generate complex cell pools with endogenously tagged proteins amenable to high-throughput visualization and perturbation. Pooled imaging coupled to in situ barcode sequencing identified the subcellular localization of each HaloTag-tagged protein, and subsequent ligand-induced misfolding of the library followed by single-cell RNA sequencing revealed responses to spatially restricted protein misfolding. These datasets characterized protein quality control responses in previously uninterrogated cellular compartments, and cross-compartment analyses revealed mutually exclusive rather than collaborative responses, whereby the heat shock response (HSR) is induced in some compartments and repressed in others where autophagy genes are induced. We further assign protein quality control functions to previously uncharacterized genes based on shared transcriptional responses to protein misfolding across cellular compartments. Altogether, we present an efficient method for large-scale studies of proteome dynamics, function, and homeostasis.
    Keywords:  hydrophobic targeting; in situ sequencing; pooled tagging; protein localization; protein misfolding; proteostasis
    DOI:  https://doi.org/10.1016/j.molcel.2025.04.002
  16. J Biol Chem. 2025 Apr 22. pii: S0021-9258(25)00382-5. [Epub ahead of print] 108533
    Phosphorylation modulates secondary structure of intrinsically disorder regions in RNA polymerase II.
    Wei Chen, Tatiana N Laremore, Neela H Yennawar, Scott A Showalter.
      The intrinsically disordered C-terminal domain (CTD) of RNA polymerase II contains tandem repeats with the consensus sequence YSPTSPS and coordinates transcription and co-transcriptional events through dynamic phosphorylation patterns. While it has been long hypothesized that phosphorylation induces structural changes in the CTD, a direct comparison of how different phosphorylation patterns modulate the CTD conformation has been limited. Here, we generated two distinct phosphorylation patterns in an essential Drosophila CTD region with the kinase Dyrk1a: one where Ser2 residues are primarily phosphorylated, mimicking the state near transcription termination, and a hyperphosphorylation state where most Ser2, Ser5, and Thr residues are phosphorylated, expanding on our work on Ser5 phosphorylation, which mimics early transcription elongation. Using 13C Direct-Detect NMR, we show that the CTD tends to form transient beta strands and beta turns, which are altered differently by Ser2 and Ser5 phosphorylation. Small angle x-ray scattering (SAXS) revealed no significant changes in the CTD global dimensions even at high phosphorylation levels, contradicting the common assumption of phosphorylation-induced chain expansion. Our findings support a transient beta model in which unphosphorylated CTD adopts transient beta strands at Ser2 during transcription pre-initiation. These transient structures are disrupted by Ser5 phosphorylation in early elongation, and later restored by Ser2 phosphorylation near termination for recruiting beta turn-recognizing termination factors.
    DOI:  https://doi.org/10.1016/j.jbc.2025.108533
  17. Nature. 2025 Apr 23.
    BMAL1-HIF2A heterodimer modulates circadian variations of myocardial injury.
    Wei Ruan, Tao Li, In Hyuk Bang, Jaewoong Lee, Wankun Deng, Xinxin Ma, Cong Luo, Fang Du, Seung-Hee Yoo, Boyun Kim, Jiwen Li, Xiaoyi Yuan, Katherine Figarella, Yu A An, Yin-Ying Wang, Yafen Liang, Matthew DeBerge, Dongze Zhang, Zhen Zhou, Yanyu Wang, Joshua M Gorham, Jonathan G Seidman, Christine E Seidman, Sary F Aranki, Ragini Nair, Lei Li, Jagat Narula, Zhongming Zhao, Alemayehu A Gorfe, Jochen D Muehlschlegel, Kuang-Lei Tsai, Holger K Eltzschig.
      Acute myocardial infarction is a leading cause of morbidity and mortality worldwide1. Clinical studies have shown that the severity of cardiac injury after myocardial infarction exhibits a circadian pattern, with larger infarcts and poorer outcomes in patients experiencing morning-onset events2-7. However, the molecular mechanisms underlying these diurnal variations remain unclear. Here we show that the core circadian transcription factor BMAL17-11 regulates circadian-dependent myocardial injury by forming a transcriptionally active heterodimer with a non-canonical partner-hypoxia-inducible factor 2 alpha (HIF2A)12-16-in a diurnal manner. To substantiate this finding, we determined the cryo-EM structure of the BMAL1-HIF2A-DNA complex, revealing structural rearrangements within BMAL1 that enable cross-talk between circadian rhythms and hypoxia signalling. BMAL1 modulates the circadian hypoxic response by enhancing the transcriptional activity of HIF2A and stabilizing the HIF2A protein. We further identified amphiregulin (AREG)16,17 as a rhythmic target of the BMAL1-HIF2A complex, critical for regulating daytime variations of myocardial injury. Pharmacologically targeting the BMAL1-HIF2A-AREG pathway provides cardioprotection, with maximum efficacy when aligned with the pathway's circadian phase. These findings identify a mechanism governing circadian variations of myocardial injury and highlight the therapeutic potential of clock-based pharmacological interventions for treating ischaemic heart disease.
    DOI:  https://doi.org/10.1038/s41586-025-08898-z
  18. Cell Rep. 2025 Apr 23. pii: S2211-1247(25)00388-2. [Epub ahead of print]44(5): 115617
    PI3K/AKT signaling mediates stress-inducible amyloid formation through c-Myc.
    Emma Lacroix, Evgenia A Momchilova, Sahil Chandhok, Mythili Padavu, Richard Zapf, Timothy E Audas.
      In response to environmental stress, eukaryotic cells reversibly form functional amyloid aggregates called amyloid bodies (A-bodies). While these solid-like biomolecular condensates share many biophysical characteristics with pathological amyloids, A-bodies are non-toxic, and they induce a protective state of cellular dormancy. As a recently identified structure, the modulators of A-body biogenesis remain uncharacterized, with the seeding noncoding RNA being the only known regulatory factor. Here, we use an image-based high-throughput screening approach to identify candidate pathways regulating A-body biogenesis. Our data demonstrate that the phosphatidylinositol 3-kinase (PI3K)/AKT signaling axis meditates A-body formation during stress exposure, with AKT activation repressing glycogen synthase kinase-3 (GSK3)-mediated degradation of c-Myc. This enhances c-Myc binding to regulatory elements of the seeding noncoding RNA, upregulating the transcripts that nucleate A-body formation. Identifying a link between PI3K/AKT signaling, c-Myc, and physiological amyloid aggregates extends the range of activity for these well-established regulators while providing insight into cellular components whose dysregulation could underly amyloidogenic disorders.
    Keywords:  Akt; CP: Cell biology; CP: Neuroscience; PI3K; amyloids; biomolecular condensates; c-Myc; environmental stress; heat shock; noncoding RNA; nucleolus; signal transduction
    DOI:  https://doi.org/10.1016/j.celrep.2025.115617
  19. J Cell Sci. 2025 Apr 15. pii: jcs263786. [Epub ahead of print]138(8):
    Epithelial cell extrusion at a glance.
    Aline Grata, Romain Levayer.
      The robustness and plasticity of epithelial tissues rely on the capacity of such tissues to eliminate cells without affecting their sealing. This is achieved by epithelial cell extrusion - a well-orchestrated series of remodelling steps involving the eliminated cell and its neighbours - which ensures the constant maintenance of mechanical and chemical barrier properties while allowing cell expulsion. In this Cell Science at a Glance and the accompanying poster, we describe the remodelling steps that take place within dying or extruding cells, as well as neighbouring cells, outlining the commonalities and variations between tissues and organisms. These steps include reorganization of the cytoskeleton and remodelling of cell-cell junctions that alters their contribution to mechanical coupling and mechanotransduction. We also discuss larger-scale coordination between cells and the contribution of cell extrusion to tissue morphogenesis, epithelial surveillance mechanisms, and pathologies such as cancer and chronic inflammation. Altogether, we outline the complexity and plasticity of this minimalist morphogenetic process.
    Keywords:  Actomyosin; Apoptosis; Caspases; Cell extrusion; Cell–cell adhesion; Epithelium; Junctions
    DOI:  https://doi.org/10.1242/jcs.263786
  20. Cell Metab. 2025 Apr 18. pii: S1550-4131(25)00211-6. [Epub ahead of print]
    Protein O-GlcNAcylation and hexokinase mitochondrial dissociation drive heart failure with preserved ejection fraction.
    Yuki Tatekoshi, Amir Mahmoodzadeh, Jason S Shapiro, Mingyang Liu, George M Bianco, Ayumi Tatekoshi, Spencer Duncan Camp, Adam De Jesus, Navid Koleini, Santiago De La Torre, J Andrew Wasserstrom, Wolfgang H Dillmann, Benjamin R Thomson, Kenneth C Bedi, Kenneth B Margulies, Samuel E Weinberg, Hossein Ardehali.
      Heart failure with preserved ejection fraction (HFpEF) is a common cause of morbidity and mortality worldwide, but its pathophysiology remains unclear. Here, we report a mouse model of HFpEF and show that hexokinase (HK)-1 mitochondrial binding in endothelial cells (ECs) is critical for protein O-GlcNAcylation and the development of HFpEF. We demonstrate increased mitochondrial dislocation of HK1 within ECs in HFpEF mice. Mice with deletion of the mitochondrial-binding domain of HK1 spontaneously develop HFpEF and display impaired angiogenesis. Spatial proximity of dislocated HK1 and O-linked N-acetylglucosamine transferase (OGT) causes increased OGT activity, shifting the balance of the hexosamine biosynthetic pathway intermediates into the O-GlcNAcylation machinery. EC-specific overexpression of O-GlcNAcase and an OGT inhibitor reverse angiogenic defects and the HFpEF phenotype, highlighting the importance of protein O-GlcNAcylation in the development of HFpEF. Our study demonstrates a new mechanism for HFpEF through HK1 cellular localization and resultant protein O-GlcNAcylation, and provides a potential therapy for HFpEF.
    Keywords:  HFpEF; O-GlcNAcylation; endothelial cell; hexokinase 1; mitochondria
    DOI:  https://doi.org/10.1016/j.cmet.2025.04.001
  21. Nat Cell Biol. 2025 Apr 22.
    Effects of embryonic origin, tissue cues and pathological signals on fibroblast diversity in humans.
    Marta Torregrossa, Lindsay Davies, Machens Hans-Günther, Jan C Simon, Sandra Franz, Yuval Rinkevich.
      Fibroblasts, once perceived as a uniform cell type, are now recognized as a mosaic of distinct populations with specialized roles in tissue homeostasis and pathology. Here we provide a global overview of the expanding compendium of fibroblast cell types and states, their diverse lineage origins and multifaceted functions across various human organs. By integrating insights from developmental biology, lineage tracing and single-cell technologies, we highlight the complex nature of fibroblasts. We delve into their origination from embryonic mesenchyme and tissue-resident populations, elucidating lineage-specific behaviours in response to physiological cues. Furthermore, we highlight the pivotal role of fibroblasts in orchestrating tissue repair, connective tissue remodelling and immune modulation across diverse pathologies. This knowledge is essential to develop novel fibroblast-targeted therapies to restore steady-state fibroblast function and advance regenerative medicine strategies across multiple diseases.
    DOI:  https://doi.org/10.1038/s41556-025-01638-5
  22. Science. 2025 Apr 25. 388(6745): eadj0430
    Distinct adipose progenitor cells emerging with age drive active adipogenesis.
    Guan Wang, Gaoyan Li, Anying Song, Yutian Zhao, Jiayu Yu, Yifan Wang, Wenting Dai, Martha Salas, Hanjun Qin, Leonard Medrano, Joan Dow, Aimin Li, Brian Armstrong, Patrick T Fueger, Hua Yu, Yi Zhu, Mengle Shao, Xiwei Wu, Lei Jiang, Judith Campisi, Xia Yang, Qiong A Wang.
      Starting at middle age, adults often suffer from visceral adiposity and associated adverse metabolic disorders. Lineage tracing in mice revealed that adipose progenitor cells (APCs) in visceral fat undergo extensive adipogenesis during middle age. Thus, despite the low turnover rate of adipocytes in young adults, adipogenesis is unlocked during middle age. Transplantations quantitatively showed that APCs in middle-aged mice exhibited high adipogenic capacity cell-autonomously. Single-cell RNA sequencing identified a distinct APC population, the committed preadipocyte, age-enriched (CP-A), emerging at this age. CP-As demonstrated elevated proliferation and adipogenesis activity. Pharmacological and genetic manipulations indicated that leukemia inhibitory factor receptor signaling was indispensable for CP-A adipogenesis and visceral fat expansion. These findings uncover a fundamental mechanism of age-dependent adipose remodeling, offering critical insights into age-related metabolic diseases.
    DOI:  https://doi.org/10.1126/science.adj0430
  23. Nature. 2025 Apr 23.
    Deciphering disordered regions controlling mRNA decay in high-throughput.
    Joseph H Lobel, Nicholas T Ingolia.
      Intrinsically disordered regions within proteins drive specific molecular functions despite lacking a defined structure1,2. Although disordered regions are integral to controlling mRNA stability and translation, the mechanisms underlying these regulatory effects remain unclear3. Here we reveal the molecular determinants of this activity using high-throughput functional profiling. Systematic mutagenesis across hundreds of regulatory disordered elements, combined with machine learning, reveals a complex pattern of molecular features important for their activity. The presence and arrangement of aromatic residues strongly predicts the ability of seemingly diverse protein sequences to influence mRNA stability and translation. We further show how many of these regulatory elements exert their effects by engaging core mRNA decay machinery. Our results define molecular features and biochemical pathways that explain how disordered regions control mRNA expression and shed light on broader principles within functional, unstructured proteins.
    DOI:  https://doi.org/10.1038/s41586-025-08919-x
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