bims-ginsta Biomed News
on Genome instability
Issue of 2025–06–01
29 papers selected by
Jinrong Hu, National University of Singapore
  1. Myocardium and endocardium of the early mammalian heart tube arise from independent multipotent lineages specified at the primitive streak.
  2. Donor embryonic stem cells displace host cells of 8-cell stage chimeras to the extraembryonic lineages by spatial crowding and FGF4 signalling.
  3. Mouse liver assembloids model periportal architecture and biliary fibrosis.
  4. Mitochondrial clonal mosaicism encodes a biphasic molecular clock of aging.
  5. Chromosomal instability in development and disease: Beyond cancer evolution.
  6. Transcriptional repression facilitates RNA:DNA hybrid accumulation at DNA double-strand breaks.
  7. RNF20 links the DNA damage response and metabolic rewiring in lung cancer through HIF1α.
  8. Expansion in situ genome sequencing links nuclear abnormalities to aberrant chromatin regulation.
  9. The nucleolar granular component mediates genome-nucleolus interactions and establishes their repressive chromatin states.
  10. Conservation of regulatory elements with highly diverged sequences across large evolutionary distances.
  11. PIEZO1-mediated calcium signaling reinforces mechanical properties of hair follicle stem cells to promote quiescence.
  12. Disrupted endosomal trafficking of the Vangl-Celsr polarity complex underlies congenital anomalies in Xenopus trachea-esophageal morphogenesis.
  13. USP37 protects mammalian cells during DNA replication stress by counteracting CUL2LRR1 and TRAIP.
  14. TRIM37 prevents ectopic spindle pole assembly by peptide motif recognition and substrate-dependent oligomerization.
  15. Catalytic-dependent and independent functions of the histone acetyltransferase CBP promote pioneer-factor-mediated zygotic genome activation.
  16. Restoring calcium crosstalk between ER and mitochondria promotes intestinal stem cell rejuvenation through autophagy in aged Drosophila.
  17. CoQ imbalance drives reverse electron transport to disrupt liver metabolism.
  18. FACT weakens the nucleosomal barrier to transcription and preserves its integrity by forming a hexasome-like intermediate.
  19. Age-associated decline of Coenzyme A leads to intestinal stem cells dysfunction via disturbing iron homeostasis.
  20. Mesoscale regulation of microtubule-organizing centers by the E3 ligase TRIM37.
  21. In vivo structure profiling reveals human cytosolic and mitochondrial tRNA structurome and interactome in response to stress.
  22. WNK1 mediates M-CSF-induced macropinocytosis to enforce macrophage lineage fidelity.
  23. Choroid plexus apocrine secretion shapes CSF proteome during mouse brain development.
  24. Efficient and multiplexed somatic genome editing with Cas12a mice.
  25. WNT-induced association of Frizzled and LRP6 is not sufficient for the initiation of WNT/β-catenin signaling.
  26. De novo assembly of nuclear stress bodies rearranges and enhances NFIL3 to restrain acute inflammatory responses.
  27. Rapid and efficient protocol for optical clearing of mouse intestinal tissues for enhanced fluorescence imaging and 3D reconstruction.
  28. Astrocyte morphogenesis requires self-recognition.
  29. Cross-organ metabolite production and consumption in healthy and atherogenic conditions.
  1. Dev Cell. 2025 May 20. pii: S1534-5807(25)00292-8. [Epub ahead of print]
    Myocardium and endocardium of the early mammalian heart tube arise from independent multipotent lineages specified at the primitive streak.
    Miquel Sendra, Katie McDole, Juan de Dios Hourcade, Susana Temiño, Morena Raiola, Léo Guignard, Philipp J Keller, Jorge N Domínguez, Miguel Torres.
      The formation of the primitive heart tube from cardiomyocytes and endocardial cells is a key event in mammalian development. Previous studies suggested that cardiomyocytes and endocardial cells segregate from a shared cardiac progenitor around the onset of gastrulation, yet their lineage relationship with other mesodermal tissues remains unclear. Using retrospective and prospective clonal analyses in mouse embryos, we traced cardiomyocyte and endocardial progenitors from the primitive streak to the heart tube. Our results identify two independent mesodermal populations specified around gastrulation onset. While each of these populations is unipotent in producing cardiomyocytes or endocardium, they retain multipotency and contribute to different subsets of non-cardiac mesoderm. Nonetheless, live imaging identifies simultaneous ingression and intermingling of these two mesodermal lineages in the primitive streak, showing their coordinated specification and migration. The proposed model for cardiac progenitor specification will help understanding the origins of congenital heart diseases and designing tissue engineering strategies.
    Keywords:  cardiac progenitors; cardiomyocytes; cell fate; clonal analysis; endocardial cells; heart development; lineage specification; lineage tracing; live imaging; mesoderm
    DOI:  https://doi.org/10.1016/j.devcel.2025.05.002
  2. Development. 2025 May 30. pii: dev.204518. [Epub ahead of print]
    Donor embryonic stem cells displace host cells of 8-cell stage chimeras to the extraembryonic lineages by spatial crowding and FGF4 signalling.
    Stanley E Strawbridge, Anna Katharina Schrattel, Peter Humphreys, Kenneth A Jones, Jérôme Artus, Anna-Katerina Hadjantonakis, Alexander G Fletcher, Jennifer Nichols.
      Following mouse embryo compaction, outer cells become trophectoderm, while inner cells form the inner cell mass (ICM), later differentiating into primitive endoderm and epiblast during blastocyst formation. Trophectoderm specification is driven by position-governed polarisation, while primitive endoderm specification is positively regulated by FGF4 signalling from the unspecified ICM and epiblast. When injected into an 8-cell stage morula, Embryonic stem cells (ESCs, derived from preimplantation epiblast cells in vitro) can exclude host cells from the epiblast, leading to mice derived entirely from these cells. While evidence suggests roles for ESC-produced FGF4 and physical crowding in host cell displacement from the ICM, the interplay between these possible mechanisms has yet to be dissected, in part due to the lack of studies using Fgf4-/- ESCs. Here, we combine chimera titration assays with mathematical modelling to study these mechanisms of host cell displacement. Both Fgf4+/+ and Fgf4-/- ESCs displaced host cells from the epiblast, while only Fgf4-/- injected embryos reduced primitive endoderm and increased trophectoderm, indicating sequential exclusion by displacement crowding followed by FGF4 signalling.
    Keywords:  Bayesian inference.; Epiblast; Mathematical modelling; Mouse embryo; Primitive endoderm; Trophectoderm
    DOI:  https://doi.org/10.1242/dev.204518
  3. Nature. 2025 May 29.
    Mouse liver assembloids model periportal architecture and biliary fibrosis.
    Anna M Dowbaj, Aleksandra Sljukic, Armin Niksic, Cedric Landerer, Julien Delpierre, Haochen Yang, Aparajita Lahree, Ariane C Kühn, David Beers, Helen M Byrne, Sarah Seifert, Heather A Harrington, Marino Zerial, Meritxell Huch.
      Modelling liver disease requires in vitro systems that replicate disease progression1,2. Current tissue-derived organoids fail to reproduce the complex cellular composition and tissue architecture observed in vivo3. Here, we describe a multicellular organoid system composed of adult hepatocytes, cholangiocytes and mesenchymal cells that recapitulates the architecture of the liver periportal region and, when manipulated, models aspects of cholestatic injury and biliary fibrosis. We first generate reproducible hepatocyte organoids with functional bile canaliculi network that retain morphological features of in vivo tissue. By combining these with cholangiocytes and portal fibroblasts, we generate assembloids that mimic the cellular interactions of the periportal region. Assembloids are functional, consistently draining bile from bile canaliculi into the bile duct. Strikingly, manipulating the relative number of portal mesenchymal cells is sufficient to induce a fibrotic-like state, independently of an immune compartment. By generating chimeric assembloids of mutant and wild-type cells, or after gene knockdown, we show proof-of-concept that our system is amenable to investigating gene function and cell-autonomous mechanisms. Taken together, we demonstrate that liver assembloids represent a suitable in vitro system to study bile canaliculi formation, bile drainage, and how different cell types contribute to cholestatic disease and biliary fibrosis, in an all-in-one model.
    DOI:  https://doi.org/10.1038/s41586-025-09183-9
  4. Nat Aging. 2025 May 27.
    Mitochondrial clonal mosaicism encodes a biphasic molecular clock of aging.
    Zhenguo Wang, Zhe Li, Hongyu Liu, Chenghua Yang, Xin Li.
      Mitochondria rapidly accumulate mutations throughout a lifetime, potentially acting as a molecular clock for aging and disease. We profiled mitochondrial RNA across 47 human tissues from 838 individuals, revealing rapid development of clonal mosaicism with two distinct tissue-specific aging signatures. Tissues with constant cellular turnover such as the gastrointestinal tract or skin exhibit accelerated accumulation of sporadic mutations and clonal expansions, implicating increased susceptibility to age-related tumorigenesis and dysfunction. By contrast, post-mitotic tissues, such as the heart and brain, accumulate mutations at deterministic hotspots (tissue-specific, recurrently mutated sites), reflecting the cumulative burden of high energy demand and mitochondrial turnover independent of cell division. These findings support a biphasic model of the mitochondrial clock: stochastic clonal expansion of sporadic replication errors in proliferative tissues, versus age-dependent heteroplasmy increases at hotspots in high-metabolic tissues. This mutational landscape provides a map of tissue-specific vulnerabilities during aging and offers potential therapeutic targets.
    DOI:  https://doi.org/10.1038/s43587-025-00890-6
  5. Curr Opin Cell Biol. 2025 May 28. pii: S0955-0674(25)00075-4. [Epub ahead of print]95 102537
    Chromosomal instability in development and disease: Beyond cancer evolution.
    Marco Milán.
      Chromosomal instability (CIN), an increased rate of changes in chromosome structure and number, has been classically associated with human disease as a way of evolving the cancer genome. In recent years, three additional research lines concerning the impact of CIN on human disease have been consolidated. First, beyond the generation of genomic copy number heterogeneity, CIN acts as a source of tumor growth, metastasis, and malignancy through additional mechanisms. Second, CIN is pervasive in early human development, and the resulting aneuploid cells are selectively removed from the fetus to give rise to healthy births. Third, CIN is associated with mosaic variegated aneuploidy, a rare familial disease that compromises brain development and contributes to tumor formation. Here, I will review recent advances in these three topics, with a particular focus on the use of model systems and organisms to understand the increasing impact of CIN on human biology and disease.
    DOI:  https://doi.org/10.1016/j.ceb.2025.102537
  6. Nat Cell Biol. 2025 May 30.
    Transcriptional repression facilitates RNA:DNA hybrid accumulation at DNA double-strand breaks.
    Florian Saur, Emma Lesage, Lea Pradel, Sarah Collins, Anne-Laure Finoux, Emile Alghoul, Benjamin Le Bozec, Vincent Rocher, Romane Carette, Nadine Puget, Marie Couralet, Melanie Petiot, Thomas Clouaire, Aline Marnef, Gaëlle Legube.
      RNA:DNA hybrids accumulate at DNA double-strand breaks (DSBs) and were shown to regulate homologous recombination repair. The mechanism responsible for the formation of these non-canonical RNA:DNA structures remains unclear although they were proposed to arise consequently to RNA polymerase II or III loading followed by DSB-induced de novo transcription at the break site. Here, we found no evidence of RNA polymerase recruitment at DSBs. Rather, strand-specific R-loop mapping revealed that RNA:DNA hybrids are mainly generated at DSBs occurring in transcribing loci, from the hybridization of pre-existing RNA to the 3' overhang left by DNA end resection. We further identified the H3K4me3 reader spindlin 1 and the transcriptional regulator PAF1 as factors promoting RNA:DNA hybrid accumulation at DSBs, through their role in mediating transcriptional repression in cis to DSBs. Altogether, we provide evidence that RNA:DNA hybrids accumulate at DSBs occurring in transcribing loci as a result of DSB-induced transcriptional shut down.
    DOI:  https://doi.org/10.1038/s41556-025-01669-y
  7. Nat Commun. 2025 May 28. 16(1): 4929
    RNF20 links the DNA damage response and metabolic rewiring in lung cancer through HIF1α.
    Hao Liu, Yongqin Tang, Anshu Singh, Joaquim Vong, Julio Cordero, Arthur Mathes, Rui Gao, Yanhan Jia, Boyan K Garvalov, Till Acker, Gernot Poschet, Rüdiger Hell, Marc A Schneider, Joerg Heineke, Thomas Wieland, Guillermo Barreto, Adelheid Cerwenka, Michael Potente, Sofia-Iris Bibli, Rajkumar Savai, Gergana Dobreva.
      Defective DNA repair and metabolic rewiring are highly intertwined in promoting the development and progression of cancer. However, the molecular players at their interface remain poorly understood. Here we show that an RNF20-HIF1α axis links the DNA damage response and metabolic reprogramming in lung cancer. We demonstrate that RNF20, which catalyzes monoubiquitylation of histone H2B (H2Bub1), controls Rbx1 expression and thereby the activity of the VHL ubiquitin ligase complex and HIF1α levels. Ablation of a single Rnf20 allele significantly increases the incidence of lung tumors in mice. Mechanistically, Rnf20 haploinsufficiency results in inadequate tumor suppression via the Rnf20-H2Bub1-p53 axis and induces DNA damage, cell growth, epithelial-mesenchymal transition (EMT), and metabolic rewiring through HIF1α-mediated RNA polymerase II promoter-proximal pause release, which is independent of H2Bub1. Importantly, decreased RNF20 levels correlate with increased expression of HIF1α and its target genes, suggesting HIF1α inhibition as a promising therapeutic approach for lung cancer patients with reduced RNF20 activity.
    DOI:  https://doi.org/10.1038/s41467-025-60223-4
  8. Science. 2025 May 29.
    Expansion in situ genome sequencing links nuclear abnormalities to aberrant chromatin regulation.
    Ajay S Labade, Zachary D Chiang, Caroline Comenho, Paul L Reginato, Andrew C Payne, Andrew S Earl, Rojesh Shrestha, Fabiana M Duarte, Ehsan Habibi, Ruochi Zhang, George M Church, Edward S Boyden, Fei Chen, Jason D Buenrostro.
      Microscopy and genomics are used to characterize cell function, but approaches to connect the two types of information are lacking, particularly at subnuclear resolution. Here, we describe expansion in situ genome sequencing (ExIGS), a technology that enables sequencing of genomic DNA and superresolution localization of nuclear proteins in single cells. Applying ExIGS to progeria-derived fibroblasts revealed that lamin abnormalities are linked to hotspots of aberrant chromatin regulation that may erode cell identity. Lamin was found to generally repress transcription, suggesting variation in nuclear morphology may affect gene regulation across tissues and aged cells. These results demonstrate that ExIGS may serve as a generalizable platform to link nuclear abnormalities to gene regulation, offering insights into disease mechanisms.
    DOI:  https://doi.org/10.1126/science.adt2781
  9. Mol Cell. 2025 May 17. pii: S1097-2765(25)00409-5. [Epub ahead of print]
    The nucleolar granular component mediates genome-nucleolus interactions and establishes their repressive chromatin states.
    Shivani Gupta, Cristiana Bersaglieri, Dominik Bär, Mathieu Raingeval, Luana Schaab, Raffaella Santoro.
      Repressive chromatin domains often localize to the nuclear lamina or nucleolus. Although nucleolar-associated domains (NADs) have recently been mapped, their mechanisms of nucleolar association and functional significance remain unclear. Here, we show that nucleophosmin (NPM1), a factor located in the granular component of the nucleolus, mediates NAD association in mouse embryonic stem cells. NPM1 binds NADs, interacts with the histone methyltransferase G9a (EHMT2), and is required for establishing H3K9me2 at NADs. Loss of NPM1 or expression of a DNA-binding-deficient mutant disrupts NAD-nucleolus association and reduces H3K9me2 specifically at NADs. G9a is dispensable for NAD-nucleolus contacts, indicating that H3K9me2 is acquired after NADs associate with NPM1 at nucleoli. These findings reveal mechanistic insights into how genomic domains associate with nucleoli and form repressive chromatin and indicate that the nucleolus not only serves as a scaffold for positioning repressive domains but also plays a direct role in establishing their repressive chromatin states.
    Keywords:  G9a; H3K9me2; NADs; NPM1; chromatin; genome organization; nucleolus
    DOI:  https://doi.org/10.1016/j.molcel.2025.05.004
  10. Nat Genet. 2025 May 27.
    Conservation of regulatory elements with highly diverged sequences across large evolutionary distances.
    Mai H Q Phan, Tobias Zehnder, Fiona Puntieri, Andreas Magg, Blanka Majchrzycka, Milan Antonović, Hannah Wieler, Bai-Wei Lo, Damir Baranasic, Boris Lenhard, Ferenc Müller, Martin Vingron, Daniel M Ibrahim.
      Developmental gene expression is a remarkably conserved process, yet most cis-regulatory elements (CREs) lack sequence conservation, especially at larger evolutionary distances. Some evidence suggests that CREs at the same genomic position remain functionally conserved independent of sequence conservation. However, the extent of such positional conservation remains unclear. Here, we profiled the regulatory genome in mouse and chicken embryonic hearts at equivalent developmental stages and found that most CREs lack sequence conservation. To identify positionally conserved CREs, we introduced the synteny-based algorithm interspecies point projection, which identifies up to fivefold more orthologs than alignment-based approaches. We termed positionally conserved orthologs 'indirectly conserved' and showed that they exhibited chromatin signatures and sequence composition similar to sequence-conserved CREs but greater shuffling of transcription factor binding sites between orthologs. Finally, we validated indirectly conserved chicken enhancers using in vivo reporter assays in mouse. By overcoming alignment-based limitations, we revealed widespread functional conservation of sequence-divergent CREs.
    DOI:  https://doi.org/10.1038/s41588-025-02202-5
  11. Sci Adv. 2025 May 30. 11(22): eadt2771
    PIEZO1-mediated calcium signaling reinforces mechanical properties of hair follicle stem cells to promote quiescence.
    Jingjing Wang, Chaoyu Fu, Sophie Chang, Christopher Stephens, Haimin Li, Dongmei Wang, Yuheng C Fu, Kathleen J Green, Jie Yan, Rui Yi.
      The mechanisms by which epithelial stem cells (SCs) sense mechanical cues within their niche and convert the information into biochemical signals to govern their function are not well understood. Here, we show that hair follicle SCs (HF-SCs) sense mechanical forces through cell adhesion and maintain quiescence in a PIEZO1-dependent mechanism. PIEZO1 interacts with E-cadherin in HF-SCs, and mechanical pulling of E-cadherin with a force of ~20 pN triggers PIEZO1-dependent, localized calcium flickers. Deletion of Piezo1 leads to reduced cumulative calcium influx and compromises quiescence. Single-cell genomic analyses identify a transcriptional network involving AP1 and NFATC1, which functions downstream of PIEZO1 and regulates the expression of extracellular matrix, cell adhesion, and actin cytoskeleton genes to reinforce the unique mechanical property of HF-SCs. These findings establish the force threshold necessary for PIEZO1 activation and reveal PIEZO1-dependent calcium influx as a key mechanism for sensing mechanical cues in the niche and regulating HF-SC activity.
    DOI:  https://doi.org/10.1126/sciadv.adt2771
  12. Dev Cell. 2025 May 21. pii: S1534-5807(25)00286-2. [Epub ahead of print]
    Disrupted endosomal trafficking of the Vangl-Celsr polarity complex underlies congenital anomalies in Xenopus trachea-esophageal morphogenesis.
    Nicole A Edwards, Scott A Rankin, Adhish Kashyap, Alissa Warren, Zachary N Agricola, Alan P Kenny, Matthew Kofron, Yufeng Shen, Wendy K Chung, Aaron M Zorn.
      Disruptions in foregut morphogenesis can result in life-threatening conditions where the trachea and esophagus fail to separate, such as esophageal atresia (EA) and tracheoesophageal fistulas (TEFs). The developmental basis of these congenital anomalies is poorly understood, but recent genome sequencing reveals that de novo variants in intracellular trafficking genes are enriched in EA/TEF patients. Here, we confirm that mutation of orthologous genes in Xenopus disrupts trachea-esophageal separation similar to EA/TEF patients. The Rab11a recycling endosome pathway is required to localize Vangl-Celsr polarity complexes at the luminal cell surface where opposite sides of the foregut tube fuse. Partial loss of endosomal trafficking or Vangl-Celsr complexes disrupts epithelial polarity and cell division orientation. Mutant cells accumulate at the fusion point, fail to relocalize cadherin, and do not separate into distinct trachea and esophagus. These data provide insights into the mechanisms of congenital anomalies and general paradigms of tissue fusion during organogenesis.
    Keywords:  EA/TEF; Rab11a; esophageal atresia; esophagus; foregut morphogenesis; trachea; tracheoesophageal fistula
    DOI:  https://doi.org/10.1016/j.devcel.2025.04.026
  13. Cell Rep. 2025 May 22. pii: S2211-1247(25)00510-8. [Epub ahead of print]44(6): 115739
    USP37 protects mammalian cells during DNA replication stress by counteracting CUL2LRR1 and TRAIP.
    Fabrizio Villa, Johanna Ainsworth, Karim P M Labib.
      The USP37 deubiquitylase is essential for mammalian cells to survive DNA replication stress, but the underlying mechanisms are unknown. Here, we demonstrate that USP37 binds the CDC45-MCM-GINS (CMG) helicase, which forms the stable core of the replisome until DNA replication termination when CMG is ubiquitylated and disassembled. USP37 contacts CDC45, and structure-guided mutations that displace USP37 from CMG cause sensitivity to DNA synthesis defects or topological stress. Binding to CDC45 at replication forks enables USP37 to counteract CMG ubiquitylation by the CUL2LRR1 ligase, which subsequently induces replisome disassembly during termination. Correspondingly, depletion of CUL2LRR1 suppresses the sensitivity of Usp37 mutants to DNA synthesis defects and ATR checkpoint kinase inhibitors. In contrast, mutation of the TRAIP ubiquitin ligase specifically suppresses the sensitivity of Usp37 mutants to topological stress. We propose that USP37 protects mammalian cells from replication stress by reversing the untimely action of the CUL2LRR1 and TRAIP ubiquitin ligases.
    Keywords:  ATR checkpoint kinase; CMG helicase; CP: Molecular biology; CUL2(LRR1); DNA replication; TRAIP; USP37; deubiquitylase; ubiquitylation
    DOI:  https://doi.org/10.1016/j.celrep.2025.115739
  14. Nat Struct Mol Biol. 2025 May 25.
    TRIM37 prevents ectopic spindle pole assembly by peptide motif recognition and substrate-dependent oligomerization.
    Andrew Bellaart, Amanda Brambila, Jiawei Xu, Francisco Mendez Diaz, Amar Deep, John Anzola, Franz Meitinger, Midori Ohta, Kevin D Corbett, Arshad Desai, Karen Oegema.
      Tightly controlled duplication of centrosomes, the primary microtubule-organizing centers of animal cells, ensures bipolarity of the mitotic spindle and accurate chromosome segregation. The RING-B-box-coiled coil ubiquitin ligase tripartite motif-containing protein 37 (TRIM37), whose loss is associated with elevated chromosome missegregation and the tumor-prone human developmental disorder Mulibrey nanism, prevents the formation of ectopic spindle poles assembling around structured condensates that contain the centrosomal protein centrobin. Here, we show that TRIM37's tumor necrosis factor receptor-associated factor (TRAF) domain, which is unique in the extended TRIM family, engages peptide motifs in centrobin to suppress condensate formation. TRIM family proteins form antiparallel coiled-coil dimers with RING-B-box domains at each end. Oligomerization resulting from RING-RING interactions and conformational regulation through B-box 2-B-box 2 interfaces are essential for TRIM37 to suppress centrobin condensate formation. These results indicate that, similar to antiviral TRIM ligases, TRIM37 activation is coupled to detection of oligomerized substrates, facilitated by recognition of specific motifs in the substrate, to enforce ubiquitination-mediated clearance of ectopic centrosomal protein assemblies.
    DOI:  https://doi.org/10.1038/s41594-025-01562-0
  15. Mol Cell. 2025 May 22. pii: S1097-2765(25)00414-9. [Epub ahead of print]
    Catalytic-dependent and independent functions of the histone acetyltransferase CBP promote pioneer-factor-mediated zygotic genome activation.
    Audrey J Marsh, Sergei Pirogov, Yadwinder Kaur, Abby J Ruffridge, Suresh Sajwan, Tyler J Gibson, George Hunt, Melissa M Harrison, Mattias Mannervik.
      Immediately after fertilization, the genome is transcriptionally quiescent. Maternally encoded pioneer factors reprogram the chromatin state and facilitate transcription of the zygotic genome. In Drosophila, transcription is initiated by the pioneer factor Zelda. While Zelda-occupied sites are enriched with histone acetylation, a post-translational mark associated with active cis-regulatory regions, the functional relationship between Zelda and histone acetylation remained unclear. We show that Zelda-mediated recruitment of the histone acetyltransferase CREB-binding protein (CBP) is essential for zygotic transcription. CBP catalytic activity is necessary for the release of RNA polymerase II (RNA Pol II) into elongation and for embryonic development. However, CBP also activates transcription independent of acetylation through RNA Pol II recruitment. Neither CBP-mediated acetylation nor CBP itself is required for the pioneering function of Zelda. Our data suggest that pioneer-factor-mediated recruitment of CBP is a conserved mechanism required to activate zygotic transcription but is separable from the function of pioneer factors in restructuring chromatin accessibility.
    Keywords:  Drosophila; RNA polymerase; histone acetyltransferase; pioneer factor; transcription; zygotic genome activation
    DOI:  https://doi.org/10.1016/j.molcel.2025.05.009
  16. Nat Commun. 2025 May 27. 16(1): 4909
    Restoring calcium crosstalk between ER and mitochondria promotes intestinal stem cell rejuvenation through autophagy in aged Drosophila.
    Yao Zhang, Peng Ma, Saifei Wang, Shuxin Chen, Hansong Deng.
      Breakdown of calcium network is closely associated with cellular aging. Previously, we found that cytosolic calcium (CytoCa2+) levels were elevated while mitochondrial calcium (MitoCa2+) levels were decreased and associated with metabolic shift in aged intestinal stem cells (ISCs) of Drosophila. How MitoCa2+ was decoupled from the intracellular calcium network and whether the reduction of MitoCa2+ drives ISC aging, however, remains unresolved. Here, we show that genetically restoring MitoCa2+ can reverse ISC functional decline and promote intestinal homeostasis by activating autophagy in aged flies. Further studies indicate that MitoCa2+ and Mitochondria-ER contacts (MERCs) form a positive feedback loop via IP3R to regulate autophagy independent of AMPK. Breakdown of this loop is responsible for MitoCa2+ reduction and ISC dysfunction in aged flies. Our results identify a regulatory module for autophagy initiation involving calcium crosstalk between the ER and mitochondria, providing a strategy to treat aging and age-related diseases.
    DOI:  https://doi.org/10.1038/s41467-025-60196-4
  17. Nature. 2025 May 28.
    CoQ imbalance drives reverse electron transport to disrupt liver metabolism.
    Renata L S Goncalves, Zeqiu Branden Wang, Jillian K Riveros, Güneş Parlakgül, Karen E Inouye, Grace Yankun Lee, Xiaorong Fu, Jani Saksi, Clement Rosique, Sheng Tony Hui, Mar Coll, Ana Paula Arruda, Shawn C Burgess, Isabel Graupera, Gökhan S Hotamışlıgil.
      Mitochondrial reactive oxygen species (mROS) are central to physiology1,2. Excess mROS production has been associated with several disease states2,3; however, the precise sources, regulation and mechanism of generation in vivo remain unclear, which limits translational efforts. Here we show that in obesity, hepatic coenzyme Q (CoQ) synthesis is impaired, which increases the CoQH2 to CoQ (CoQH2/CoQ) ratio and drives excessive mROS production through reverse electron transport (RET) from site IQ in complex I. Using multiple complementary genetic and pharmacological models in vivo, we demonstrate that RET is crucial for metabolic health. In patients with steatosis, the hepatic CoQ biosynthetic program is also suppressed, and the CoQH2/CoQ ratio positively correlates with disease severity. Our data identify a highly selective mechanism for pathological mROS production in obesity, which can be targeted to protect metabolic homeostasis.
    DOI:  https://doi.org/10.1038/s41586-025-09072-1
  18. Mol Cell. 2025 May 15. pii: S1097-2765(25)00407-1. [Epub ahead of print]
    FACT weakens the nucleosomal barrier to transcription and preserves its integrity by forming a hexasome-like intermediate.
    Francesca Burgos-Bravo, Alexander B Tong, Chen Li, César Díaz-Celis, Craig D Kaplan, Gary LeRoy, Danny Reinberg, Carlos Bustamante.
      Transcription of yeast RNA polymerase II through nucleosomes requires the assistance of the histone chaperone FACT (facilitates chromatin transcription). Yet, how FACT modulates the nucleosomal mechanical barrier to affect the polymerase's elongation dynamics is poorly understood. Using high-resolution single-molecule optical tweezers, we show that FACT greatly decreases the magnitude of the barrier by favoring the unwrapping of DNA from the distal H2A-H2B dimer, which, in turn, weakens the contacts near the dyad, significantly reducing the enzyme's crossing time. We show that barrier crossing depends on the asymmetric flexibility of the nucleosome arms, an asymmetry we find across the genome. Mechanical unwrapping of Cy3-H2A nucleosomes reveals that FACT reduces their unwrapping force and stabilizes a hexasome-like intermediate that retains both labeled dimers during successive unwrapping cycles. This intermediate is also observed after transcription. In conclusion, FACT facilitates nucleosomal transcription by weakening the barrier and actively assisting the maintenance of nucleosomal integrity after enzyme passage.
    Keywords:  FACT; RNA polymerase II; histone chaperone; nucleosomal DNA flexibility; nucleosome; nucleosome integrity; nucleosome unwrapping; optical tweezers; single-molecule fluorescence; transcription
    DOI:  https://doi.org/10.1016/j.molcel.2025.05.002
  19. PLoS Genet. 2025 May 30. 21(5): e1011704
    Age-associated decline of Coenzyme A leads to intestinal stem cells dysfunction via disturbing iron homeostasis.
    Zhiming Liu, Gang Du, Yi Chen, Haiyang Chen.
      The decline in adult stem cell performance is closely linked to tissue malfunction and the rising incidence of age-related diseases. To investigate the molecular basis of these impairments, our screening strategy identified reduced activity in the pantothenate/coenzyme A (CoA) pathway within aged ISCs. Furthermore, exogenous CoA supplementation restructured ISC metabolic pathways, reversing age-induced hyperproliferation and intestinal dysfunction, and thus extending Drosophila lifespan by curbing excessive iron accumulation in ISCs. These findings uncover a new mechanism of stem cell aging and propose that pantothenate and CoA could be potential therapeutic targets for treating age-related diseases and enhancing healthy aging in humans.
    DOI:  https://doi.org/10.1371/journal.pgen.1011704
  20. Nat Struct Mol Biol. 2025 May 25.
    Mesoscale regulation of microtubule-organizing centers by the E3 ligase TRIM37.
    Zhong Y Yeow, Sonia Sarju, Fang-Chi Chang, Lance Y Xu, Mark van Breugel, Andrew J Holland.
      Centrosomes ensure accurate chromosome segregation during cell division. Although the regulation of centrosome number is well established, less is known about the suppression of noncentrosomal microtubule-organizing centers (ncMTOCs). The E3 ligase TRIM37, implicated in Mulibrey nanism and 17q23-amplified cancers, has emerged as a key regulator of both centrosomes and ncMTOCs. Yet, the mechanism by which TRIM37 achieves enzymatic activation to target these mesoscale structures had thus far remained unknown. Here we elucidate the activation process of TRIM37, unveiling a process that initiates with TRAF domain-directed substrate recognition followed by B-box domain-mediated oligomerization and culminates in RING domain dimerization. Using optogenetics, we demonstrate that the E3 activity of TRIM37 is directly coupled to the assembly state of its substrates, being activated only when centrosomal proteins cluster into higher-order assemblies resembling MTOCs. This regulatory framework provides a mechanistic basis for understanding TRIM37-driven pathologies and echoes the restriction of the human immunodeficiency virus capsid by TRIM5, thus unveiling a conserved activation blueprint among TRIM proteins to control turnover of complexes assembled at the mesoscale level.
    DOI:  https://doi.org/10.1038/s41594-025-01540-6
  21. Nat Commun. 2025 May 30. 16(1): 5041
    In vivo structure profiling reveals human cytosolic and mitochondrial tRNA structurome and interactome in response to stress.
    Noah Peña, Yichen Hou, Christopher P Watkins, Sihao Huang, Wen Zhang, Christopher D Katanski, Tao Pan.
      Transfer RNA (tRNA) is the most abundant cellular RNA family in terms of copy numbers. It not only folds into defined structures but also has complex cellular interaction networks involving aminoacyl-tRNA synthetases, translation factors, and ribosomes. The human tRNAome is comprised of chromosomal-encoded tRNAs with a large sequence diversity and mitochondrial-encoded tRNAs with A/U-rich sequences and noncanonical tertiary interactions. How tRNA folding and interactions in a eukaryotic cell respond to stress is poorly understood. Here, we develop DM-DMS-MaPseq, which utilizes in vivo dimethyl-sulfate (DMS) chemical probing and mutational profiling (MaP) coupled with demethylase (DM) treatment in transcriptome-wide tRNA sequencing to profile structures and the cellular interactions of human chromosomal and mitochondrial-encoded tRNAs. We found that tRNAs maintain stable structures in vivo, but the in vivo DMS profiles are vastly different from those in vitro, which can be explained by their interactions with cellular proteins and the ribosome. We also identify cytosolic and mitochondrial tRNA structure and interaction changes upon arsenite treatment, a type of oxidative stress that induces translational reprogramming, which is consistent with global translation repression in both compartments. Our results reveal variations of tRNA structurome and dynamic interactome that have functional consequences in translational regulation.
    DOI:  https://doi.org/10.1038/s41467-025-59435-5
  22. Nat Commun. 2025 May 28. 16(1): 4945
    WNK1 mediates M-CSF-induced macropinocytosis to enforce macrophage lineage fidelity.
    Alissa J Trzeciak, Zong-Lin Liu, Mohamed Gatie, Adam S Krebs, Waleska Saitz Rojas, Anya J O'Neal, Ann K Baako, Zhaoquan Wang, Justin Nelson, Isabella C Miranda, Jazib Uddin, Allie Lipshutz, Jian Xie, Chou-Long Huang, Pedro H V Saavedra, Anna-Katerina Hadjantonakis, Michael Overholtzer, Michael S Glickman, Arohan R Subramanya, Thomas Vierbuchen, Jon Iker Etchegaray, Christopher D Lucas, Christopher N Parkhurst, Justin S A Perry.
      Tissue-resident macrophages (TRM) are critical for mammalian organismal development and homeostasis. Here we report that with-no-lysine 1 (WNK1) controls myeloid progenitor fate, with Csf1riCre-mediated Wnk1 deletion in mice (WNK1-deficient mice) resulting in loss of TRMs and causing perinatal mortality. Mechanistically, absence of WNK1 or inhibition of WNK kinase activity disrupts macrophage colony-stimulating factor (M-CSF)-stimulated macropinocytosis, thereby blocking mouse and human progenitor and monocyte differentiation into macrophages and skewing progenitor differentiation into neutrophils. Treatment with PMA rescues macropinocytosis but not macrophage differentiation of WNK-inhibited progenitors, implicating that M-CSF-stimulated, macropinocytosis-induced activation of WNK1 is required for macrophage differentiation. Finally, M-CSF-stimulated macropinocytosis triggers WNK1 nuclear translocation and concomitant increased protein expression of interferon regulatory factor (IRF)8, whereas inhibition of macropinocytosis or WNK kinase activity suppresses IRF8 expression. Our results thus suggest that WNK1 and downstream IRF8-regulated genes are important for M-CSF/macropinocytosis-mediated regulation of myeloid cell lineage commitment during TRM development and homeostasis.
    DOI:  https://doi.org/10.1038/s41467-025-59901-0
  23. Nat Neurosci. 2025 May 28.
    Choroid plexus apocrine secretion shapes CSF proteome during mouse brain development.
    Ya'el Courtney, Joshua P Head, Neil Dani, Olga V Chechneva, Frederick B Shipley, Yong Zhang, Michael J Holtzman, Cameron Sadegh, Towia A Libermann, Maria K Lehtinen.
      The choroid plexus (ChP) regulates cerebrospinal fluid (CSF) composition, providing essential molecular cues for brain development; yet, embryonic ChP secretory mechanisms remain poorly defined. Here we identify apocrine secretion by embryonic ChP epithelial cells as a key regulator of the CSF proteome and neurodevelopment in male and female mice. We demonstrate that the activation of serotonergic 5-HT2C receptors (by WAY-161503) triggers sustained Ca2+ signaling, driving high-volume apocrine secretion in mouse and human ChP. This secretion alters the CSF proteome, stimulating neural progenitors lining the brain's ventricles and shifting their developmental trajectory. Inducing ChP secretion in utero in mice disrupts neural progenitor dynamics, cerebral cortical architecture and offspring behavior. Additionally, illness or lysergic acid diethylamide exposure during pregnancy provokes coordinated ChP secretion in the mouse embryo. Our findings reveal a fundamental secretory pathway in the ChP that shapes brain development, highlighting how its disruption can have lasting consequences for brain health.
    DOI:  https://doi.org/10.1038/s41593-025-01972-9
  24. Nat Biomed Eng. 2025 May 30.
    Efficient and multiplexed somatic genome editing with Cas12a mice.
    Jess D Hebert, Haiqing Xu, Yuning J Tang, Paloma A Ruiz, Colin R Detrick, Jing Wang, Nicholas W Hughes, Oscar Donosa, Vicky P Siah, Laura Andrejka, Saswati Karmakar, Irenosen Aboiralor, Rui Tang, Rocio Sotillo, Julien Sage, Le Cong, Dmitri A Petrov, Monte M Winslow.
      Somatic genome editing in mouse models has increased our understanding of the in vivo effects of genetic alterations. However, existing models have a limited ability to create multiple targeted edits, hindering our understanding of complex genetic interactions. Here we generate transgenic mice with Cre-regulated and constitutive expression of enhanced Acidaminococcus sp. Cas12a (enAsCas12a), which robustly generates compound genotypes, including diverse cancers driven by inactivation of trios of tumour suppressor genes or an oncogenic translocation. We integrate these modular CRISPR RNA (crRNA) arrays with clonal barcoding to quantify the size and number of tumours with each array, as well as the impact of varying the guide number and position within a four-guide array. Finally, we generate tumours with inactivation of all combinations of nine tumour suppressor genes and find that the fitness of triple-knockout genotypes is largely explainable by one- and two-gene effects. These Cas12a alleles will enable further rapid creation of disease models and high-throughput investigation of coincident genomic alterations in vivo.
    DOI:  https://doi.org/10.1038/s41551-025-01407-7
  25. Nat Commun. 2025 May 24. 16(1): 4848
    WNT-induced association of Frizzled and LRP6 is not sufficient for the initiation of WNT/β-catenin signaling.
    Jan Hendrik Voss, Zsombor Koszegi, Yining Yan, Emily Shorter, Lukas Grätz, Johanna T Lanner, Davide Calebiro, Gunnar Schulte.
      The Wingless/Int-1 (WNT) signaling network is essential to orchestrate central physiological processes such as embryonic development and tissue homeostasis. In the currently held tenet, WNT/β-catenin signaling is initiated by WNT-induced recruitment of Frizzleds (FZDs) and LRP5/6 followed by the formation of a multiprotein signalosome complex. Here, we use bioluminescence resonance energy transfer (BRET) to show that different WNT paralogs dynamically trigger FZD-LRP6 association. While WNT-induced receptor interaction was independent of C-terminal LRP6 phosphorylation, it was allosterically modulated by binding of the phosphoprotein Dishevelled (DVL) to FZD. WNT-16B emerged as a ligand of particular interest, as it efficiently promoted FZD-LRP6 association but, unlike WNT-3A, did not lead to WNT/β-catenin signaling. Transcriptomic analysis further revealed distinct transcriptional fingerprints of WNT-3A and WNT-16B stimulation in HEK293 cells. Additionally, single-molecule tracking demonstrated that, despite increasing FZD5 and LRP6 confinement, WNT-16B stimulation did not result in formation of higher-order receptor clusters, in contrast to WNT-3A. Our results suggest that FZD-WNT-LRP5/6 complex formation alone is not sufficient for the initiation of WNT/β-catenin signaling. Instead, we propose a two-step model, where initial ligand-induced FZD-LRP6 association must be followed by receptor clustering into higher-order complexes and subsequent phosphorylation of LRP6 for efficient activation of WNT/β-catenin signaling.
    DOI:  https://doi.org/10.1038/s41467-025-60096-7
  26. Cell. 2025 May 19. pii: S0092-8674(25)00514-8. [Epub ahead of print]
    De novo assembly of nuclear stress bodies rearranges and enhances NFIL3 to restrain acute inflammatory responses.
    Xiao-Qi Liu, Pan Li, Bao-Qing Gao, Heng-Le Zhu, Liang-Zhong Yang, Yang Wang, Yu-Yao Zhang, Hao Wu, Yu-Hang Pan, Lin Shan, Hongtao Yu, Li Yang, Ling-Ling Chen.
      The membrane-less nuclear stress bodies (nSBs), with satellite III (SatIII) RNAs as the hallmark, are present in primates upon sensing stresses. We report that SatⅢ DNAs, SatⅢ RNAs, and 30 nSB proteins assemble into well-organized structures shortly after stresses. The activated SatⅢ heterochromatin loci rapidly expand, resulting in reduced spatial distance and enhanced expression of adjacent genes, including the transcription suppressor NFIL3, which is known to dampen proinflammatory cytokine production. Rearranging NFIL3 loci within the nSB territory enhances NFIL3 chromatin accessibility and makes NFIL3 promoters more accessible to transcription factors heat shock transcription factor 1 (HSF1) and bromodomain containing 4 (BRD4), which are also recruited to nSBs upon stresses. Human peripheral blood mononuclear cell (PBMC)-derived macrophages under heat shock plus pathogen-associated molecular pattern treatments exhibit increased SatⅢ and NFIL3 expression, the latter of which suppresses key inflammatory cytokines. Importantly, NFIL3 expression positively correlates with SatⅢ activation in septic patients, a process positively correlated to patient survival, highlighting a role of nSBs in restraining inflammatory responses.
    Keywords:  NFIL3; inflammatory response; nuclear bodies; nuclear stress bodies; satellite III; transcription regulation
    DOI:  https://doi.org/10.1016/j.cell.2025.05.003
  27. STAR Protoc. 2025 May 28. pii: S2666-1667(25)00247-3. [Epub ahead of print]6(2): 103841
    Rapid and efficient protocol for optical clearing of mouse intestinal tissues for enhanced fluorescence imaging and 3D reconstruction.
    Joel Johnson George, Sierra H Ball, Elena Wang, Remy T Schneider, Claudia Capdevila, Francesca Martini, Hyeonjeong Lee, Jonathan Miller, Liang Cheng, John W Murray, Hans-Willem Snoeck, Kelley S Yan.
      Histological analysis of intestinal epithelial tissues is enhanced by 3D visualization compared to 2D sections. Here, we present a protocol for 3D visualization of intestinal epithelial cells using an optical clearing approach optimized for endogenous fluorescence and preservation of crypt-villus morphology. We describe steps for clearing and refractive index matching tissue. We provide detailed procedures for imaging and reconstructing tissue to visualize epithelial cells along the crypt-villus axis with high resolution. We illustrate this approach with endogenous tdTomato used for lineage tracing in the small intestine of Fgfbp1-CreERT2; Rosa26-tdTomato mice. For complete details on the use and execution of this protocol, please refer to Capdevila et al.1.
    Keywords:  Cell Biology; Cell Differentiation; Microscopy; Stem Cells
    DOI:  https://doi.org/10.1016/j.xpro.2025.103841
  28. Nature. 2025 May 28.
    Astrocyte morphogenesis requires self-recognition.
    John H Lee, Alina P Sergeeva, Göran Ahlsén, Seetha Mannepalli, Fabiana Bahna, Kerry M Goodman, Runzhe Xu, Baljit S Khakh, Joshua A Weiner, Lawrence Shapiro, Barry Honig, S Lawrence Zipursky.
      Self-recognition is a fundamental cellular process across evolution and forms the basis of neuronal self-avoidance1-4. Clustered protocadherin (cPcdh) proteins, which comprise a large family of isoform-specific homophilic recognition molecules, have a pivotal role in the neuronal self-avoidance that is required for mammalian brain development5-7. The probabilistic expression of different cPcdh isoforms confers unique identities on neurons and forms the basis for neuronal processes to discriminate between self and non-self5,6,8. Whether this self-recognition mechanism also exists in astrocytes remains unknown. Here we report that γC3, a specific isoform in the Pcdhγ family, is enriched in human and mouse astrocytes. Using genetic manipulation, we demonstrate that γC3 acts autonomously to regulate astrocyte morphogenesis in the mouse visual cortex. To determine whether γC3 proteins act by promoting recognition between processes of the same astrocyte, we generated pairs of γC3 chimeric proteins that are capable of heterophilic binding to each other, but incapable of homophilic binding. Co-expression of complementary heterophilic binding isoform pairs in the same γC3-null astrocyte restored normal morphology. By contrast, chimeric γC3 proteins individually expressed in single γC3-null mutant astrocytes did not. These data establish that self-recognition mediated by γC3 contributes to astrocyte development in the mammalian brain.
    DOI:  https://doi.org/10.1038/s41586-025-09013-y
  29. Cell. 2025 May 20. pii: S0092-8674(25)00512-4. [Epub ahead of print]
    Cross-organ metabolite production and consumption in healthy and atherogenic conditions.
    Hosung Bae, Sunhee Jung, Johnny Le, Ian Tamburini, Joohwan Kim, Eric Wang, Won-Suk Song, Wonsuk Choi, Ki-Hong Jang, Taekyung Kang, Miranda L Lopez, Cuauhtemoc Ramirez, Ipsita Mohanty, Miranda E Kelly, Jessie Kim, Raymond Kim, Sang Hee Park, Jongwon Baek, Bryan Mendez, Paul Petrus, Thomas Q de Aguiar Vallim, Dequina A Nicholas, Quinton Smith, Gina Lee, Marcus Seldin, Cholsoon Jang.
      Mammalian organs continuously produce and consume circulating metabolites for organismal health and survival. However, the landscape of this fundamental process and its perturbation by diet and disease is unknown. Using arteriovenous metabolomics, tissue transcriptomics, and hormone arrays in multiple pathophysiological conditions in pigs, we generated an atlas of 10 cross-organ metabolite production and consumption during fasting/feeding, Western diet, and cardiovascular disease progression induced by low-density lipoprotein receptor (LDLR) deficiency. We discovered numerous instances of feeding-dependent and -independent metabolite production and consumption by organs and proposed mechanisms by which these are disrupted by Western diet via altered metabolite concentration gradients and hormones. Both Western diet and LDLR deficiency trigger the release of bile acids (BAs) by extra-hepatic organs, likely contributing to abnormally elevated circulating BA levels and consequent vascular inflammation and atherosclerosis development. These resources reveal intricate inter-organ metabolic crosstalk across pathophysiological conditions, offering biochemical insights into diet effects and cardiometabolic diseases.
    Keywords:  arteriovenous metabolomics; bile acid metabolism; cardiovascular disease; circulating metabolite; flux; inter-organ exchange; isotope tracing; low-density lipoprotein receptor; metabolomics; western diet
    DOI:  https://doi.org/10.1016/j.cell.2025.05.001
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