bims-crepig Biomed News
on Chromatin regulation and epigenetics in cell fate and cancer
Issue of 2025–12–14
twelve papers selected by
Connor Rogerson, University of Cambridge
  1. Molecular and epistatic interactions between pioneer transcription factors shape nucleosome dynamics and cell differentiation.
  2. Nanoscale dynamics of enhancer-promoter interactions during exit from pluripotency.
  3. Feed-forward loops by NR5A2 ensure robust gene activation during pre-implantation development.
  4. OTX2 controls chromatin accessibility to direct somatic versus germline differentiation.
  5. H3K36 Methylation as a Guardian of Epigenome Integrity.
  6. BPTF regulates androgen receptor activity by enhancing chromatin accessibility and stabilizing the AR-FOXA1 interaction.
  7. Co-condensation between transcription factor and cBAF selectively modulates chromatin remodeling and gene expression.
  8. Recognition of two hydrophobic pockets in the KIX domain of CBP by FOXO4 transactivation domain.
  9. Intrinsically disordered regions facilitate target search to drive promoter selectivity by a yeast transcription factor.
  10. Genome-wide nucleosome and transcription factor responses to genetic perturbations reveal chromatin-mediated mechanisms of transcriptional regulation.
  11. SEdb 3.0: a comprehensive super-enhancer database across multiple species.
  12. Conservation of cis-regulatory codes over half a billion years of evolution.
  1. Nat Commun. 2025 Dec 10.
    Molecular and epistatic interactions between pioneer transcription factors shape nucleosome dynamics and cell differentiation.
    Rémi-Xavier Coux, Agnès Dubois, Almira Chervova, Inma Gonzalez, Sandrine Vandormael-Pournin, Michel Cohen-Tannoudji, Pablo Navarro.
      Pioneer transcription factors (TF) bind nucleosome-embedded DNA motifs to activate new regulatory elements and promote differentiation. However, the complexity, binding dependencies and temporal effects of their action remain unclear. Here, we dissect how ectopic induction of the pioneer TF GATA6 triggers Primitive Endoderm (PrE) differentiation from pluripotent cells. We show that transient GATA6 binding exploits accessible regions to decommission enhancers and promote pluripotency gene silencing. Simultaneously, GATA6 targets closed chromatin and initiates extensive remodeling culminating in the establishment of fragile nucleosomes flanked by ordered nucleosome arrays and increased accessibility. This is enhanced by rapidly expressed PrE TFs (SOX17) and by pluripotency TFs repurposed for differentiation (OCT4/SOX2). Accordingly, depletion of OCT4 during GATA6 induction decreases Gata6 expression, alters GATA6 and SOX17 binding and impairs differentiation. Therefore, pioneer TFs orchestrate complex regulatory networks involving many if not all available pioneer TFs, including those required to support the original identity of differentiating cells.
    DOI:  https://doi.org/10.1038/s41467-025-67308-0
  2. Nucleic Acids Res. 2025 Nov 26. pii: gkaf1255. [Epub ahead of print]53(22):
    Nanoscale dynamics of enhancer-promoter interactions during exit from pluripotency.
    Gabriela Stumberger, David Hörl, Dimitra Tsouraki, Clemens Steinek, A Marieke Oudelaar, Heinrich Leonhardt, Hartmann Harz.
      While compelling genetic evidence supports the role of enhancers in regulating promoter activity even over large genomic distances, it remains unclear to what extent physical proximity to promoters is required. To address this, we combined fluorescence in situ hybridization (FISH) with super-resolution microscopy and Tri-C to examine enhancer-promoter (E-P) distances and regulatory element clustering at regulated loci (Nanog, Dppa3, Dnmt3a, Sox2, Prdm14) during the transition from naive to primed pluripotency in mouse embryonic stem cells. Despite transcriptional changes of several orders of magnitude, most genes show no major alterations in median E-P distances or in the probability of multiway contacts across states. However, Tri-C reveals a weak enrichment of multiway contacts at Nanog in naive cells, where it is highly expressed. Because transcription often occurs in transient bursts within a subset of cells, we combined RNA and DNA FISH to identify active alleles. For Nanog and Dppa3, reduced E-P distances correlate with transcriptional activity. Together, these findings support models in which transcription is associated with transient E-P proximity and suggest that multiway contact formation among regulatory elements may contribute to gene regulation.
    DOI:  https://doi.org/10.1093/nar/gkaf1255
  3. Development. 2025 Dec 08. pii: dev.205059. [Epub ahead of print]
    Feed-forward loops by NR5A2 ensure robust gene activation during pre-implantation development.
    Wataru Kobayashi, Siwat Ruangroengkulrith, Eda Nur Arslantas, Adarsh Mohanan, Kikuë Tachibana.
      Pioneer transcription factors are crucial for regulating zygotic genome activation and cell differentiation during mouse pre-implantation development. However, how pioneer factors function collectively to regulate early development remains poorly understood. Here, we determined the chromatin binding profiles of the pioneer factor NR5A2 during the totipotency-to-pluripotency transition and identified KLF and GATA family transcription factors as key co-regulators. NR5A2 regulates the expression of Klf5 and Gata6, whose proteins in turn act as co-regulators of NR5A2 to promote development. Mechanistically, KLF5 contributes to H3K27ac deposition at genomic regions co-occupied by NR5A2. NR5A2 also regulates Xist expression, either directly or indirectly, through its role in co-binding with GATA factors and up-regulating their expression. In vitro assays revealed that NR5A2 binds to nucleosomes with KLF5 and GATA6, suggesting that these pioneer factors can simultaneously bind to chromatin. Our findings provide evidence for a feed-forward regulatory mechanism by which NR5A2 activates expression of lineage-determining factors and these, together with NR5A2, subsequently co-bind nucleosomes to ensure robust gene activation during pre-implantation development.
    Keywords:  Lineage-determining factor; Nuclear receptor; Pioneer transcription factor; Pre-implantation development; Transcriptional regulation
    DOI:  https://doi.org/10.1242/dev.205059
  4. EMBO Rep. 2025 Dec 08.
    OTX2 controls chromatin accessibility to direct somatic versus germline differentiation.
    Elisa Barbieri, Ian Chambers.
      The choice between somatic and germline fates is essential for species survival. This choice occurs in embryonic epiblast cells, as these cells are competent for both somatic and germline differentiation. The transcription factor OTX2 regulates this process, as Otx2-null epiblast-like cells (EpiLCs) form primordial germ cell-like cells (PGCLCs) with enhanced efficiency. Yet, how OTX2 achieves this function is not fully characterised. Here we show that OTX2 controls chromatin accessibility at specific chromatin loci to enable somatic differentiation. CUT&RUN for OTX2 and ATAC-seq in wild-type and Otx2-null embryonic stem cells and EpiLCs identifies regions where OTX2 binds and opens chromatin. Enforced OTX2 expression maintains accessibility at these regions and also induces opening of ~4000 somatic-associated regions in cells differentiating in the presence of PGC-inducing cytokines. Once cells have acquired germline identity, these additional regions no longer respond to OTX2 and remain closed. Our results indicate that OTX2 works in cells with dual competence for somatic and germline differentiation to increase accessibility of somatic regulatory regions and induce the somatic fate at the expense of the germline.
    Keywords:  Chromatin Accessibility; Formative Pluripotency; Germline; OTX2
    DOI:  https://doi.org/10.1038/s44319-025-00622-2
  5. Nat Commun. 2025 Dec 11.
    H3K36 Methylation as a Guardian of Epigenome Integrity.
    Reinnier Padilla, Gerry A Shipman, Cynthia Horth, Michel Gravel, Eric Bareke, Jacek Majewski.
      H3K36 methylation is a key epigenetic mark with critical roles in development and disease. Here, we systematically dissect its functions using CRISPR-engineered mouse mesenchymal stem cells lacking combinations of the five H3K36 methyltransferases, culminating in quintuple knockout cells devoid of H3K36me2/3. We show that H3K36me2 influences enhancer activity, supports the expression of their target genes, and safeguards active genes from encroachment of the repressive marks, H3K27me2/3. In addition, we find that the loss of H3K36me triggers redistribution of large heterochromatic H3K9me3 domains into euchromatin, in part mediated by SUV39H1, leading to global epigenomic remodelling, constitutive heterochromatin erosion, and a collapse of 3D genome organization. Parallel analyses in human HNSCC cells overexpressing the H3K36M oncohistone reveal conserved disruptions to the epigenome and chromatin architecture. Together, these results establish H3K36 methylation as a pivotal regulator of chromatin state and genomic structure.
    DOI:  https://doi.org/10.1038/s41467-025-66365-9
  6. Nat Commun. 2025 Dec 11.
    BPTF regulates androgen receptor activity by enhancing chromatin accessibility and stabilizing the AR-FOXA1 interaction.
    Hee-Young Jeon, Sudeep Khadka, Majid Pornour, Hyunju Ryu, Hegang Chen, Arif Hussain, Hung-Ming Lam, Eva Corey, Htoo Zarni Oo, Martin Gleave, Xiaofang Che, Christopher Barbieri, Jianfei Qi.
      BPTF, the scaffolding subunit of the nucleosome remodeling factor (NURF) complex, has been implicated in the progression of several malignancies, but its role in prostate cancer (PCa) remains unclear. Here, we demonstrate that BPTF is upregulated in castration-resistant prostate cancer (CRPC) and promotes disease progression. RNA-seq revealed that BPTF primarily enhances the expression of androgen receptor (AR) target genes. ChIP-seq showed that BPTF increases AR binding at promoters, enhancers and super-enhancers. ATAC-seq further demonstrated that BPTF increases chromatin accessibility to facilitate AR binding, in part through SMARCA1, a catalytic subunit of the NURF complex. Notably, BPTF/AR co-bound regions are highly enriched for FOXA1 motifs but only weakly enriched for AR motifs. We further show that BPTF forms a protein complex with AR and FOXA1, in which FOXA1 recruits the BPTF-AR complex to chromatin, while BPTF stabilizes the AR-FOXA1 interaction. Importantly, BPTF interacts with AR through its bromodomain, and a BPTF bromodomain inhibitor disrupts this interaction, impairs AR signaling and suppresses PCa cell growth. In summary, our findings establish BPTF as a critical regulator of AR activity by promoting chromatin accessibility and stabilizing the AR-FOXA1 complex, highlighting BPTF as a potential therapeutic target in prostate cancer.
    DOI:  https://doi.org/10.1038/s41467-025-67329-9
  7. Nat Commun. 2025 Dec 11.
    Co-condensation between transcription factor and cBAF selectively modulates chromatin remodeling and gene expression.
    Xifu Ye, Lin Xu, Xuejiao Sun, Yanzhi Gai, Haixia Yang, Qiang Sun, Jiayi Song, Peiqi Huang, Qianru Zhou, Yaxu Li, Na Li, Jiali Jin, Yang Li, Wei Rao, Huasong Lu, Ping Wang, Chunmei Chang, Yi Lu.
      Activation of gene transcription is a tightly coordinated process that requires the engagement of transcription factors (TFs) and chromatin remodelers, yet how these components integrate at specific genomic loci remains unclear. Here, we report that ARID1A, a key subunit of the chromatin remodeler cBAF complex, forms condensates through uniformly distributed tyrosine residues within its core intrinsically disordered region (IDR). A series of TFs which feature in the presence of tyrosine within their transcription activation domain (TAD), selectively interact with ARID1A through core IDR-TAD interaction, thereby enabling co-condensation at specific loci. Furthermore, we demonstrate that co-condensation between ARID1A and TFs, such as GATA2, is crucial for maintaining chromatin accessibility and activating genes essential for lung cancer cell proliferation. Collectively, our study establishes the essential role of ARID1A in spatial organization of TFs and cBAF through phase separation, and demonstrates that tyrosine-mediated selective TFs-cBAF co-condensation represents a pivotal mechanism for gene activation.
    DOI:  https://doi.org/10.1038/s41467-025-67322-2
  8. Commun Biol. 2025 Dec 11. 8(1): 1760
    Recognition of two hydrophobic pockets in the KIX domain of CBP by FOXO4 transactivation domain.
    Jeongbeen Heo, Kyoung-Seok Ryu, Chin-Ju Park.
      The transcription machinery is assembled via interactions of DNA-bound transcriptional activators and coactivators. When the eukaryotic RNA polymerase II complex is formed, cAMP-regulated transcription factor (CREB) binding protein (CBP) acts as a general coactivator bridging the transcriptional apparatus. Forkhead box protein O4 (FOXO4), a transcription factor, has been reported to bind to the KIX domain of CBP (CBP-KIX). Although the CR3 of FOXO4 (FOXO4-CR3) binds as expected to the MLL and c-Myb sites of CBP-KIX, its substantially higher affinity for CBP, compared to its homolog FOXO3a, cannot be explained by a single conserved ΦXXΦΦ binding motif. Here, we found that a second ΦXXΦΦ motif in FOXO4-CR3 provides an additional point of contact for CBP-KIX. Isothermal titration calorimetry and chemical shift perturbation analyses revealed a difference in binding affinity and confirmed that different binding patterns occur at the two hydrophobic pockets of CBP-KIX. Increased helicity of FOXO4-CR3 upon KIX MLL site binding was demonstrated by circular dichroism and Cα chemical shifts. Paramagnetic relaxation enhancement and docking simulations suggested FOXO4-CR3 orientation is not restrained in the KIX-CR3 complex. Our study provides information about the unique binding properties of FOXO4-CR3 and CBP-KIX, expanding our understanding of CBP recruitment via KIX-transactivation domain binding.
    DOI:  https://doi.org/10.1038/s42003-025-09146-w
  9. Nat Commun. 2025 Dec 10.
    Intrinsically disordered regions facilitate target search to drive promoter selectivity by a yeast transcription factor.
    Nir Strugo, Carmit Burstein, Sk Saddam Hossain, Noam Nago, Hadeel Khamis, Ariel Kaplan.
      Transcription factors regulate gene expression by binding specific DNA motifs, yet only a fraction of putative sites is occupied in vivo. Intrinsically disordered regions have emerged as key contributors to promoter selectivity, but the underlying mechanisms remain incompletely understood. Here, we use single-molecule optical tweezers to dissect how disordered regions influence DNA binding by Msn2, a yeast stress-response regulator. We show that these regions power a search mechanism, facilitating initial non-specific association with DNA and promoting one-dimensional scanning toward target motifs, supported by charge-mediated interactions. Remarkably, this mechanism displays sequence sensitivity, with promoter-derived sequences enhancing both initial binding and scanning rates, demonstrating that Msn2-DNA interactions alone are sufficient to confer promoter selectivity in the absence of chromatin or cofactors. Our findings provide direct mechanistic evidence for how intrinsically disordered regions tune transcription factor search dynamics for Msn2 and expand sequence recognition beyond canonical motifs, supporting promoter selectivity in complex genomic contexts.
    DOI:  https://doi.org/10.1038/s41467-025-67217-2
  10. Genome Res. 2025 Dec 09.
    Genome-wide nucleosome and transcription factor responses to genetic perturbations reveal chromatin-mediated mechanisms of transcriptional regulation.
    Kevin Moyung, Yulong Li, Heather K MacAlpine, Alexander J Hartemink, David M MacAlpine.
      Epigenetic mechanisms contribute to gene regulation by altering chromatin accessibility through changes in transcription factor (TF) and nucleosome occupancy across the genome. Despite numerous studies focusing on changes in gene expression, the intricate chromatin-mediated regulatory code remains largely uncharted on a comprehensive scale. We address this by employing a factor-agnostic, reverse-genetics approach that uses MNase-seq to capture genome-wide TF and nucleosome occupancies in response to the individual deletion of 201 transcriptional regulators in Saccharomyces cerevisiae, thereby assaying nearly 1 million mutant-gene interactions. We develop a principled new approach to identify and quantify chromatin changes genome-wide, allowing us to observe differences in TF and nucleosome occupancy that recapitulate well-established pathways identified by gene expression data. We also discover distinct chromatin signatures associated with the up- and downregulation of genes and use these signatures to reveal regulatory mechanisms previously unexplored in expression-based studies. Finally, we demonstrate that chromatin features are predictive of transcriptional activity, and we leverage these features to reconstruct chromatin-based transcriptional regulatory networks. Overall, these results illustrate the power of an approach combining genetic perturbation with high-resolution epigenomic profiling; the latter enables a close examination of the interplay between TFs and nucleosomes genome-wide, providing a deeper, more mechanistic understanding of the complex relationship between chromatin organization and transcription.
    DOI:  https://doi.org/10.1101/gr.279637.124
  11. Nucleic Acids Res. 2025 Dec 08. pii: gkaf1294. [Epub ahead of print]
    SEdb 3.0: a comprehensive super-enhancer database across multiple species.
    Shuang Song, Liyuan Liu, Chenchen Feng, Liyuan Xie, Guorui Zhang, Yuexin Zhang, Yichen Gao, Mingxue Yin, Xiuyun Tang, Wenya Pei, Chao Song, Runping Liu, Chunquan Li.
      Super-enhancers (SEs) are key DNA cis-regulatory elements that play a central role in regulating tissue/cell-specific gene expression, thereby maintaining cellular identity and function. SEdb 3.0 (http://www.licpathway.net/sedb) provides an extensively updated resource of SEs and their regulatory annotations across multiple species. The current version of SEdb now curates 3 478 186 SEs from 5387 H3K27ac ChIP-seq samples across four species. Compared to SEdb 2.0, it has achieved a two-fold expansion in human and mouse SE entries while newly incorporating Arabidopsis thaliana and maize data, significantly enhancing both the database's scale and its utility in plant research. Furthermore, abundant (epi)genomic features have been added, such as enhancer RNAs (eRNAs), binding sites of transcription co-factors (TcoFs), and chromatin regulators (CRs). The inclusion of eRNAs provides insights into SE transcriptional activity. Mapping TcoF binding sites highlights their roles in mediating enhancer-promoter looping and stabilizing transcriptional complexes at SEs. The integration of CRs uncovers how SEs are associated with histone modifications and chromatin remodeling, which are critical for maintaining an open chromatin state. Collectively, these annotations not only reveal the diverse mechanisms by which SEs exert regulatory functions but also enable more detailed investigations into their biological significance and functional roles. Meanwhile, existing annotations have been substantially expanded, such as an approximately five-fold increase in transcription factor (TF) ChIP-seq data, a 2.3-fold rise in TF motifs, and a roughly 1.8-fold growth in SE-associated eQTL-gene regulatory pairs. SEdb 3.0 introduces two advanced inference strategies for associating genes with SEs. Moreover, two newly developed analysis tools are provided in SEdb 3.0, including SE blast alignment analysis and SE-driven core TF enrichment analysis. In summary, SEdb 3.0 represents a significant upgrade over SEdb 2.0, with a substantial expansion in SE coverage across multiple species, alongside enhanced functional annotations encompassing SE upstream/downstream regulatory information, thereby offering a more comprehensive and user-friendly platform for exploring the biological roles of SEs.
    DOI:  https://doi.org/10.1093/nar/gkaf1294
  12. Sci Adv. 2025 Dec 12. 11(50): eadw7681
    Conservation of cis-regulatory codes over half a billion years of evolution.
    Yohey Ogawa, Yu Liu, Connie A Myers, Ala Morshedian, Gordon L Fain, Alapakkam P Sampath, Joseph C Corbo.
      Identifying homologous cell types across species is essential for understanding cell type evolution. The retina is ideal for comparative analysis because its six major cell classes have persisted since the origin of vertebrates more than half a billion years ago. Here, we show that the retina's conserved cellular architecture is mirrored by deep conservation of the cis-regulatory codes that govern gene expression. Through single-cell chromatin accessibility analysis of lamprey, fish, bird, and mammalian retinas, we demonstrate cross-species conservation of cis-regulatory codes in all retinal cell classes despite extensive turnover of cis-regulatory regions. Conservation manifests as clustering of high-affinity transcription factor binding sites in cell class-specific open chromatin regions. Thus, the retina's cellular Bauplan is controlled by cis-regulatory codes, which predate the divergence of extant vertebrates.
    DOI:  https://doi.org/10.1126/sciadv.adw7681
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