bims-crepig Biomed News
on Chromatin regulation and epigenetics in cell fate and cancer
Issue of 2025–11–02
twelve papers selected by
Connor Rogerson, University of Cambridge
  1. FACT depletion demonstrates a role for nucleosome organization in TAD formation.
  2. Paused RNA polymerase primes promoters via RNA-mediated stabilisation of transcription factor ERα.
  3. SOX2-driven enhancer landscapes define the transcriptional architecture of retinogenesis.
  4. Pre-established ATF4 occupancy and chromatin organization instruct selective transcription activation during integrated stress response.
  5. Molecular mechanism of co-transcriptional H3K36 methylation by SETD2.
  6. Auto-inhibition of PRC2 by the broadly expressed long isoform of AEBP2.
  7. SEA version 4.0: a major expansion and update of the Super-Enhancer Archive.
  8. Cryo-EM reveals open and closed Asgard chromatin assemblies.
  9. Maternal factor OTX2 regulates human embryonic genome activation and early development.
  10. scVMAP: a comprehensive platform for integrating single-cell chromatin accessibility regions with causal variants.
  11. TET knockout cells transit between pluripotent states and exhibit precocious germline entry.
  12. Transcription factor switching drives subtype-specific pancreatic cancer.
  1. Mol Syst Biol. 2025 Oct 27.
    FACT depletion demonstrates a role for nucleosome organization in TAD formation.
    Clemens Mauksch, Yi Zhu, Taras Velychko, Spyridoula Sagropoulou, Abrar Aljahani, Shyam Ramasamy, Kristina Žumer, A Marieke Oudelaar.
      Mammalian genomes are organized into distinct chromatin structures, which include small-scale nucleosome arrays and large-scale topologically associating domains (TADs). The mechanistic interplay between chromatin structures across scales is poorly understood. Here, we investigate how changes in nucleosome organization impact TAD structure by studying the role of the histone chaperone facilitates chromatin transcription (FACT) in 3D genome organization. We show that FACT depletion perturbs TADs, causing decreased insulation and weaker CTCF loops. These changes in TAD structure cannot be attributed to changes in chromatin occupancy of CTCF or cohesin and occur specifically in transcribed regions of the genome, where we observe perturbed nucleosome organization in the absence of FACT. FACT depletion therefore allows us to separate the role of nucleosome organization and CTCF binding and to demonstrate that the organization of nucleosomes at TAD boundaries contributes to TAD formation.
    Keywords:  3D Genome Organization; CTCF; FACT; Nucleosome; Topologically Associating Domain (TAD)
    DOI:  https://doi.org/10.1038/s44320-025-00165-7
  2. Nat Commun. 2025 Oct 29. 16(1): 9553
    Paused RNA polymerase primes promoters via RNA-mediated stabilisation of transcription factor ERα.
    Rajat Mann, Deepanshu Soota, Ayan Das, Nitesh Kumar Podh, Gunjan Mehta, Dimple Notani.
      Regulated pausing of RNA polymerase II (Pol II) is essential for enabling rapid and coordinated transcriptional responses to signalling cues. Pausing also contributes to the formation of nucleosome-free regions with the help of chromatin remodellers. However, if these nucleosome-free regions engage with transcription factors to stimulate the transcription potential of paused promoters is not known. In this study, we demonstrate that ligand-induced estrogen receptor-alpha (ERα) binding is stabilized at Pol II-paused sites. This stabilization results from an increased dwell time of ERα on chromatin, as revealed by single molecule tracking (SMT) experiments. Notably, short chromatin-associated RNAs generated by the paused Pol II contribute to enhancing ERα binding at paused promoters. We also observe that pausing increases H3K27ac levels, which primes paused promoters for robust transcriptional activation upon release. Collectively, these findings suggest that paused Pol II plays a central role in enhancing transcription factor binding through an RNA-dependent mechanism. This, in turn, results in a more vigorous transcriptional response following pausing release, thus contributing to the fine-tuning of ERα-mediated gene regulation.
    DOI:  https://doi.org/10.1038/s41467-025-64569-7
  3. Development. 2025 Oct 29. pii: dev.204986. [Epub ahead of print]
    SOX2-driven enhancer landscapes define the transcriptional architecture of retinogenesis.
    Fuyun Bian, Kimiasadat Golestaneh, Emily Davis, Abdullah Khan, Brendan Nicholson, Marwa Daghsni, Keevon Flohr, Silvia Liu, Susana da Silva, Len Pennacchio, Issam Al Diri.
      Retinal neurogenesis is mediated by the coordinated activities of a complex gene regulatory network (GRN) of transcription factors (TFs) in multipotent retinal progenitor cells (RPCs). How this GRN mechanistically guides neural competence remains poorly understood. In this study, we present integrated transcriptional, genetic, and genomic analyses to uncover the regulatory mechanisms of SOX2, a key factor in establishing neural identity in RPCs. We show that SOX2 is preferentially enriched in the RPC-specific enhancer landscape associated with essential regulators of retinogenesis. Disruption of SOX2 expression impairs retinogenesis, marked by a selective loss of enhancer activity near genes essential for RPC proliferation and lineage specification. We identified the RPC transcription factor VSX2 as a binding partner for SOX2, and together, SOX2 and VSX2 co-target a core, retina-specific chromatin repertoire characterized by enhanced TF binding and robust chromatin accessibility. This cooperative binding establishes a shared SOX2-VSX2 transcriptional code that promotes the expression of critical regulators of neurogenesis while repressing the acquisition of alternative lineage cell fate. Our data illuminate fundamental biological insights on how transcription factors act in concert to drive chromatin-based genetic programs underlying retinal neural identity.
    Keywords:  Chromatin; Enhancers; Neurogenesis; Retina; Transcription
    DOI:  https://doi.org/10.1242/dev.204986
  4. Nat Commun. 2025 Oct 28. 16(1): 9502
    Pre-established ATF4 occupancy and chromatin organization instruct selective transcription activation during integrated stress response.
    Peipei Jiang, Qian Bian.
      Cells rapidly and extensively remodel their transcriptome in response to stress to restore homeostasis, but the underlying mechanisms are not fully understood. Here, we characterize the dynamic changes in transcriptome, epigenetics, and 3D genome organization during the integrated stress response (ISR). ISR induction triggers widespread transcriptional changes within 6 h, coinciding with increased binding of ATF4, a key transcriptional effector. Notably, ATF4 binds to hundreds of genes even under non-stress conditions, priming them for stronger activation upon stress. The transcriptional changes at ATF4-bound sites during ISR do not rely on increased H3K27 acetylation, chromatin accessibility, or rewired enhancer-promoter looping. Instead, ATF4-mediated gene activation is linked to the redistribution of CEBPγ from non-ATF4 sites to a subset of ATF4-bound regions, likely by forming an ATF4/CEBPγ heterodimer. CEBPγ preferentially targets the sites pre-occupied by ATF4, as well as genomic regions exhibiting a unique higher-order chromatin structure signature. Thus, the transcriptional responses during ISR are largely pre-wired by intrinsic chromatin properties. These findings provide critical insights into transcriptional remodeling during ISR with broader implications for other stress responses.
    DOI:  https://doi.org/10.1038/s41467-025-64577-7
  5. Nat Commun. 2025 Oct 29. 16(1): 9565
    Molecular mechanism of co-transcriptional H3K36 methylation by SETD2.
    James L Walshe, Moritz Ochmann, Ute Neef, Olexandr Dybkov, Christian Dienemann, Christiane Oberthür, Aiturgan Zheenbekova, Henning Urlaub, Patrick Cramer.
      H3K36me3 is a hallmark of actively and recently transcribed genes and contributes to cellular memory and identity. The deposition of H3K36me3 occurs co-transcriptionally when the methyltransferase SETD2 associates with RNA polymerase II. Here we present three cryo-EM structures of SETD2 bound to RNA polymerase II elongation complexes at different states of nucleosome passage. Together with functional probing, our results suggest a 3-step mechanism of transcription-coupled H3K36me3 deposition. First, binding to the elongation factor SPT6 tethers the catalytic SET domain in proximity to the upstream DNA. Second, RNA polymerase II nucleosome passage leads to the transfer of a hexasome from downstream to upstream, poised for methylation. Finally, continued transcription leads to upstream nucleosome reassembly, partial dissociation of the histone chaperone FACT and sequential methylation of both H3 tails, completing H3K36me3 deposition of an upstream nucleosome after RNA polymerase II passage.
    DOI:  https://doi.org/10.1038/s41467-025-65439-y
  6. EMBO J. 2025 Oct 30.
    Auto-inhibition of PRC2 by the broadly expressed long isoform of AEBP2.
    Marlena Mucha, Zhihao Lai, Nicholas J McKenzie, Francesca Matrà, Marion Boudes, Sarena F Flanigan, Maria Teresa Alejo-Vinogradova, Craig Monger, Qi Zhang, Darragh Nimmo, Evan Healy, Ademar J Silva, Daniel Angelov, David M Reck, Gráinne Holland, Zeynep Eda Atmaca, Helen E King, Maeve Hamilton, Eleanor Glancy, James Nolan, Robert J Weatheritt, Oliver Bell, Michiel Vermeulen, Chen Davidovich, Adrian P Bracken.
      Polycomb Repressive Complex 2 (PRC2) is an essential chromatin regulator responsible for mono-, di- and tri-methylating H3K27. Control of PRC2 activity is a critical process in development and disease, yet no inhibitory cofactor has been identified in somatic cells. Here, we show that the alternative isoforms of its accessory subunit AEBP2, namely AEBP2S (short) and AEBP2L (long), perform opposite functions in modulating PRC2 activity. Contrary to prior assumptions that AEBP2 enhances PRC2 function, we find that the widely expressed AEBP2L isoform inhibits it. AEBP2L is expressed throughout embryogenesis and adulthood and inhibits PRC2 DNA binding, histone methyltransferase activity, and binding to target genes. In contrast, AEBP2S, expressed during early embryogenesis, promotes PRC2 DNA-binding activity and is essential for de novo repression of target genes during the transition from naïve to primed pluripotency. Mechanistically, through high-resolution cryo-EM and mutagenesis, we show that the recently evolved, negatively charged N-terminal region of AEBP2L inhibits PRC2. We propose a scenario in which the N-terminus of AEBP2L arose in vertebrates to restrain PRC2 activity in somatic cells.
    Keywords:  AEBP2; Cryo-EM; PRC2; Polycomb; Trithorax
    DOI:  https://doi.org/10.1038/s44318-025-00616-9
  7. Nucleic Acids Res. 2025 Oct 31. pii: gkaf1114. [Epub ahead of print]
    SEA version 4.0: a major expansion and update of the Super-Enhancer Archive.
    Bowen Shi, Jiyun Zhao, Yu Li, Chenye Zhang, Longhao Deng, Chengzhi Ji, Hongli Wang, Ruiyang Zhai, Tao Feng, Yan Zhang, Yue Gu.
      Super-enhancers (SEs) are pivotal epigenetic regulatory elements that profoundly influence cell fate and disease. We herein present an updated SEA version 4.0, a systematic platform designed to elucidate the roles of SEs. A uniform computational pipeline was established to identify SEs based on five key histone marks, using H3K27ac, BRD4, p300, Med1, and the newly added H3K4me1, across 14 species. 496 071 SEs and 29 584 078 enhancers have been stored in the database. It provides extensive genome annotations, including nearby genes, transcription factor binding sites, chromatin accessibility, and other gene regulation signatures. SEA version 4.0 has also achieved functional enrichment analysis of SEs. And a Shannon entropy-based algorithm is employed to identify specific SEs. Furthermore, SEA version 4.0 introduces an interactive regulatory network that incorporates SEs, enhancers, transcription factors, and proximal genes for human and mouse. Additionally, a cell-specific SE detector is provided, designed for cancer research by leveraging scRNA-seq data from 12 cancer and normal samples to explore cell-type-specific SEs. The performance interaction and visualization of SEA version 4.0 enable genomic and cross-species comparisons, revealing complex genomic interactions and becoming an indispensable resource for decoding the mechanisms of SE in development and disease. Access freely at http://sea4.edbc.org.
    DOI:  https://doi.org/10.1093/nar/gkaf1114
  8. Mol Cell. 2025 Oct 28. pii: S1097-2765(25)00818-4. [Epub ahead of print]
    Cryo-EM reveals open and closed Asgard chromatin assemblies.
    Harsh M Ranawat, Marc K Cajili, Natalia Lopez-Barbosa, Thomas Quail, Remus T Dame, Svetlana O Dodonova.
      Asgards are the closest archaeal relatives of eukaryotes, representing an important step in chromatin evolution. However, their chromatin organization has remained enigmatic until now. In this study, we present the first structures of Asgard chromatin assemblies formed by the Hodarchaeal histone HHoB. Our high-resolution cryo-electron microscopy (cryo-EM) structures reveal that this Asgard histone assembles into compact "closed" and into extended "open" hypernucleosomes. Thus, the closed hypernucleosome conformation is conserved across archaeal lineages, while the open conformation resembles a eukaryotic H3-H4 octasome and likely represents an Asgard-specific innovation. Moreover, we show that Mg²⁺ ions influence Asgard chromatin conformation, suggesting a regulatory role. Overall, our study provides the first structure-based model of Asgard chromatin organization, expanding our understanding of chromatin architecture in an evolutionary context.
    Keywords:  Archaea; Asgard; chromatin; cryo-EM; evolution; histones; structure
    DOI:  https://doi.org/10.1016/j.molcel.2025.10.001
  9. Nat Genet. 2025 Oct 27.
    Maternal factor OTX2 regulates human embryonic genome activation and early development.
    Qiuyan Wang, Chuanxin Zhang, Yanna Dang, Jiaqi Sun, Zhuoning Zou, Cheng Li, Shuiying Ma, Zongyu Li, Hui Liu, Xiaonan Ma, Zhen Yang, Lijuan Wang, Keliang Wu, Zi-Jiang Chen, Wei Xie, Han Zhao.
      Transcription factors (TFs) are instrumental in kickstarting embryonic genome activation (EGA) in many species, yet their regulatory roles in human embryos remain poorly understood. Here, we show that OTX2, a maternally provided PRD-like homeobox TF, is required for proper human EGA and early development. At the four-cell stage, OTX2 promotes activation of key EGA genes, including TPRX1 and TPRX2, and the EGA-associated repeat HERVL-int and MLT2A1. At EGA targets, OTX2 directly binds promoters and putative enhancers, many of which overlap with Alu and MaLR repetitive elements containing the OTX2 motif, and promotes chromatin accessibility. The transcriptome and developmental defects upon OTX2 knockdown are partially rescued by overexpression of TPRX1 and TPRX2. Finally, joint knockdown of OTX2 and TPRXL, encoding another maternal PRD-like homeobox TF, exacerbates chromatin opening and EGA defects at the 8C stage. These findings establish OTX2 as a crucial maternal TF that awakes the genome at the beginning of human life.
    DOI:  https://doi.org/10.1038/s41588-025-02350-8
  10. Nucleic Acids Res. 2025 Oct 31. pii: gkaf1112. [Epub ahead of print]
    scVMAP: a comprehensive platform for integrating single-cell chromatin accessibility regions with causal variants.
    Zheng-Min Yu, Feng-Cui Qian, Qiao-Li Fang, Xiang-Yang Meng, Yan-Yu Li, Chen-Chen Feng, Li-Dong Li, Bing-Long Li, Yu-Rong Feng, Hui Jiang, Qiu-Yu Wang, Xuan Fan, Jin-Cheng Guo, Chun-Quan Li.
      Integrating causal variant effects with single-cell assay for transposase-accessible chromatin with high-throughput sequencing (scATAC-seq) enables a more effective elucidation of the roles and impacts of genetic variations at the single-cell level. With the accumulation of genome-wide association studies and single-cell genomic data, there is an urgent need for comprehensive analysis and efficient exploration of these data to uncover the underlying biological processes. To address this, we developed scVMAP (https://bio.liclab.net/scvmap/), a user-friendly database aiming to provide trait-relevant cell populations at single-cell resolution. The current version of scVMAP has integrated 183 scATAC-seq datasets and 15 884 fine-mapping results, generating more than 32.1 billion trait-cell pairs, offering valuable resources for exploring the functional localization of single-cell variations. To enhance the understanding of how phenotypic associations are mapped to single-cell data, scVMAP provides a wealth of detailed information, including trait relevance scores (TRSs) for each cell, cell-type-specific differential gene and transcription factor (TF) activities, trait-relevant gene and TF interactions, and regulatory networks linking traits to cell types. Based on these comprehensive analytical results, scVMAP offers users convenient interfaces to search, browse, analyse, and visualize relationships between traits and cell populations at single-cell resolution.
    DOI:  https://doi.org/10.1093/nar/gkaf1112
  11. EMBO J. 2025 Oct 27.
    TET knockout cells transit between pluripotent states and exhibit precocious germline entry.
    Raphaël Pantier, Elisa Barbieri, Sara Gonzalez Brito, Ella Thomson, Tülin Tatar, Douglas Colby, Man Zhang, Ian Chambers.
      TET1, TET2 and TET3 are DNA demethylases with important roles in development and differentiation. To assess the contributions of TET proteins to cell function during early development, single and compound knockouts of Tet genes in mouse pluripotent embryonic stem cells (ESCs) were generated. Here, we show that TET proteins are not required to transit between naïve, formative and primed pluripotency states. Moreover, ESCs with double knockouts of Tet1 and Tet2 or triple knockouts of Tet1, Tet2 and Tet3 are phenotypically indistinguishable. TET1,2,3-deficient ESCs exhibit differentiation defects and fail to activate somatic gene expression, retaining expression of pluripotency transcription factors. Therefore, TET1 and TET2, but not TET3 act redundantly to facilitate somatic differentiation. Importantly however, TET-deficient ESCs can differentiate into primordial germ cell-like cells (PGCLCs), and do so at high efficiency in the presence or absence of PGC-promoting cytokines. Moreover, acquisition of a PGCLC transcriptional programme occurs more rapidly in TET-deficient cells. These results establish that TET proteins act at the juncture between somatic and germline fates: without TET proteins, epiblast cell differentiation defaults to the germline.
    Keywords:  Differentiation; Pluripotency; Primordial Germ Cells; Stem Cells; TET Proteins
    DOI:  https://doi.org/10.1038/s44318-025-00597-9
  12. Nat Genet. 2025 Oct 30.
    Transcription factor switching drives subtype-specific pancreatic cancer.
    Shalini V Rao, Lisa Young, Danya Cheeseman, Sean Flynn, Niklas Krebs, Dominique-Laurent Couturier, Stephanie Mack, Rebecca Brais, Jill Temple, Amy Smith, Evangelia Papachristou, Catarina Pelicano, Chandra Sekhar Reddy Chilamakuri, Krzysztof Herka, Hideo Baba, Luay Farah, Phyllis F Cheung, Jens Siveke, Stéphane Guerrier, Luca Insolia, Michael Gill, Emily Archer Goode, Steven Kupczak, Yi Cheng, Giacomo Borsari, Duncan Jodrell, Clive D'Santos, Alasdair Russell, Barbara T Grünwald, Eva Serrao, Igor Chernukhin, Jason S Carroll.
      Emerging evidence suggests that lineage-specifying transcription factors control the progression of pancreatic ductal adenocarcinoma (PDAC). We have discovered a transcription factor switching mechanism involving the poorly characterized orphan nuclear receptor HNF4G and the putative pioneer factor FOXA1, which drives PDAC progression. Using our unbiased protein interactome discovery approach, we identified HNF4A and HNF4G as reproducible, FOXA1-associated proteins, in both preclinical models and Whipple surgical samples. In the primary tumor context, we consistently find that the dominant transcription factor is HNF4G, where it functions as the driver. A molecular switch occurs in advanced disease, whereby HNF4G expression or activity decreases, unmasking FOXA1's transcriptional potential. Derepressed FOXA1 drives late-stage disease by orchestrating metastasis-specific enhancer-promoter loops to regulate the expression of metastatic genes. Overall survival is influenced by HNF4G and FOXA1 activity in primary tumor growth and in metastasis, respectively. We suggest that the existence of stage-dependent transcription factor activity, triggered by molecular compartmentalization, mediates the progression of PDAC.
    DOI:  https://doi.org/10.1038/s41588-025-02389-7
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