bims-crepig Biomed News
on Chromatin regulation and epigenetics in cell fate and cancer
Issue of 2025–11–30
eleven papers selected by
Connor Rogerson, University of Cambridge
  1. Synergy between regulatory elements can render cohesin dispensable for distal enhancer function.
  2. Single-cell multiomics analysis reveals CTCF as a key regulator of lung morphogenesis and progenitor maintenance.
  3. Neural crest induction requires SALL4-mediated BAF recruitment to lineage specific enhancers.
  4. Motif-based models accurately predict cell type-specific distal regulatory elements.
  5. DNA bendability inside the nucleosome regulates INO80's nucleosome positioning.
  6. Addressing the specific roles of histone modifications in transcriptional repression.
  7. FoxP3 forms a head-to-head dimer in vivo and stabilizes its multimerization on adjacent microsatellites.
  8. CTCF-RNA interactions orchestrate cell-specific chromatin loop organization.
  9. Widespread association of Polycomb complex-deposited histone H2A monoubiquitylation with enhancers and neuronal gene regulation.
  10. Roles of histone chaperone Nap1 and histone acetylation in regulating phase-separation of nucleosome arrays.
  11. H3K4me2 orchestrates H2A.Z and Polycomb repressive marks in Arabidopsis.
  1. Science. 2025 Nov 27. eadt4221
    Synergy between regulatory elements can render cohesin dispensable for distal enhancer function.
    Karissa L Hansen, Annie S Adachi, Luca Braccioli, Smit Kadvani, Ryan M Boileau, Moreno Martinovic, Bozhena Pokorny, Rini Shah, Erika C Anderson, Kaite Zhang, Irié Carel, Kenya Bonitto, Robert Blelloch, Geoffrey Fudenberg, Elzo de Wit, Elphège P Nora.
      Enhancers are critical genetic elements controlling transcription from promoters, yet how they convey regulatory information across large genomic distances remains unclear. Here, we engineer pluripotent stem cells in which cohesin loop extrusion can be inducibly disrupted without confounding cell cycle defects. Transcriptional dysregulation is cell type-specific, and not all loci with distal enhancers depend equally on cohesin extrusion. Using comparative genome editing, we demonstrate that enhancer-promoter communication over just 20 kilobases can require cohesin. However, promoter-proximal elements can support long-range, cohesin-independent enhancer action - even across strong CTCF insulators. Finally, transcriptional dynamics and the emergence of embryonic cell types remain largely robust despite disrupted extrusion. Beyond establishing strategies to study cohesin in enhancer biology, our work provides mechanistic insight into cell type- and genomic context-specificity.
    DOI:  https://doi.org/10.1126/science.adt4221
  2. Nat Commun. 2025 Nov 28. 16(1): 10729
    Single-cell multiomics analysis reveals CTCF as a key regulator of lung morphogenesis and progenitor maintenance.
    Shenfei Sun, Yamei Jiang, Fujing Huang, Wei Wei, Mathias Hochgerner, Tianmin Xu, Xiaoting Wang, Kaijun Lin, Xinna Zhang, Yanli Wang, Hua He, Miao Yu, Xiaofang Tang, Xinhua Lin.
      Lung development generates a complex tree-like architecture through proximal-distal patterning and branching morphogenesis. However, the gene regulatory programs governing embryonic lung development remain poorly understood. Here, we present a comprehensive single-cell multi-omics atlas of mouse embryonic lungs, integrating gene expression and chromatin accessibility profiles. Through systematic analysis, we identify 13 distinct cell types and map cis-regulatory elements, peak-to-gene linkages, and transcription factors underlying lung development. Leveraging this multi-modal dataset, we uncover lineage-determining transcription factors driving cell differentiation, including the Activated Protein-1 complex. We further delineate gene regulatory networks involving diverse transcription regulators, including CCCTC-binding factor (CTCF). Using the Ctcf conditional knockout mouse, coupled with histological and multi-omics analyses, we demonstrate that CTCF orchestrates lung progenitor maintenance and branching morphogenesis by modulating both gene expression and chromatin accessibility. Thus, our study provides a multi-omics resource and mechanistic insights for transcriptional regulation of lung morphogenesis.
    DOI:  https://doi.org/10.1038/s41467-025-65757-1
  3. Development. 2025 Nov 28. pii: dev.205248. [Epub ahead of print]
    Neural crest induction requires SALL4-mediated BAF recruitment to lineage specific enhancers.
    Martina Demurtas, Samantha M Barnada, Emma van Domselaar, Zoe H Mitchell, Laura Deelen, Marco Trizzino.
      Neural crest induction begins early during neural plate formation, requiring precise transcriptional control to activate lineage-specific enhancers. Here, we demonstrate that SALL4, a transcription factor associated with syndromes featuring craniofacial anomalies, plays a critical role in early cranial neural crest (CNCC) specification. Using SALL4-het-KO human iPSCs to model clinical haploinsufficiency, we show that SALL4 directly recruits BAF to CNCC-lineage specific enhancers at the neuroectodermal stage, specifically when neural crest gene expression is induced at the neural plate border. Without functional SALL4, BAF is not loaded at chromatin, leaving CNCC enhancers inaccessible. Consequently, the cells cannot undergo proper CNCC induction and specification due to persistent enhancer repression, despite normal neuroectodermal and neural plate progression. Moreover, by performing SALL4 isoform-specific depletion, we demonstrate that the SALL4A is the isoform essential for CNCC induction and specification, and that SALL4B cannot compensate for SALL4A loss in this developmental process. In summary, our findings reveal SALL4 as essential regulator of BAF-dependent enhancer activation during early stages of neural crest development, providing molecular insights into SALL4-associated craniofacial anomalies.
    Keywords:  BAF; Chromatin accessibility; DPF2; Enhancers; Neural crest; SALL4; SALL4A
    DOI:  https://doi.org/10.1242/dev.205248
  4. Nat Commun. 2025 Nov 24. 16(1): 10370
    Motif-based models accurately predict cell type-specific distal regulatory elements.
    Paola Cornejo-Páramo, Xuan Zhang, Lithin Louis, Zelun Li, Yihua Yang, Emily S Wong.
      Deciphering how DNA sequence specifies cell-type-specific regulatory activity is a central challenge in gene regulation. We present Bag-of-Motifs (BOM), a computational framework that represents distal cis-regulatory elements as unordered counts of transcription factor (TF) motifs. This minimalist representation, combined with gradient-boosted trees, enables the accurate prediction of cell-type-specific enhancers across mouse, human, zebrafish, and Arabidopsis datasets. Despite its simplicity, BOM outperforms more complex deep-learning models while using fewer parameters. We validate BOM's predictions experimentally by constructing synthetic enhancers from the most predictive motifs, demonstrating that these motif sets drive cell-type-specific expression. By providing direct interpretability and broad applicability, BOM reveals a highly predictive sequence code at distal regulatory regions and offers a scalable framework for dissecting cis-regulatory grammar across diverse species and conditions.
    DOI:  https://doi.org/10.1038/s41467-025-65362-2
  5. Mol Cell. 2025 Nov 24. pii: S1097-2765(25)00827-5. [Epub ahead of print]
    DNA bendability inside the nucleosome regulates INO80's nucleosome positioning.
    Shagun Shukla, Mzwanele Ngubo, Somnath Paul, Franziska Kunert, Jim Persinger, Junwoo Lee, Karl-Peter Hopfner, Blaine Bartholomew.
      While some ATP-dependent chromatin remodelers are negatively regulated by short tracts of DNA sequences (i.e., poly d(A) or GC-rich), the INO80 chromatin remodeler is regulated by DNA not readily identified by its sequence but rather by its physical properties. The underlying reason for these differences appears to be the unique mechanism by which INO80 mobilizes nucleosomes. We find that the INO80 chromatin remodeler mobilizes nucleosomes by displacing DNA from the histone octamer and creating DNA "bulges" that translocate around the octamer in a wave-like manner. Nucleosome movement is blocked by inflexible nucleosomal DNA that interferes with the initial formation of DNA bulges and is linked to INO80's accurate positioning of nucleosomes at the +1 position of yeast gene promoters. Some of the interactions of the Arp5 subunit are lost when bound to inflexible DNA and may act as sensors to regulate INO80 remodeling in a DNA-shape-dependent manner.
    Keywords:  ATP-dependent chromatin remodeling, transcription regulation; Arp5; DNA; INO80; chromatin; chromatin remodeling; nucleosome; transcription
    DOI:  https://doi.org/10.1016/j.molcel.2025.10.010
  6. Nat Commun. 2025 Nov 22.
    Addressing the specific roles of histone modifications in transcriptional repression.
    Lin Hedehus, Aina M Mas, Aktan Alpsoy, Robin L Armstrong, Richard Koche, Tülin Tatar, Hua Wang, Kristian Helin.
      Our understanding of epigenetic processes is based on the hypothesis that individual posttranslational modifications of DNA and histones, or combinations thereof, function to direct unique downstream effects on transcription. Still, histone modifications are broadly categorized as repressive or activating, raising the question of potential functional redundancy. Here, we present an approach for addressing this question by substituting the genome-wide H3K27me3 pattern with other histone modifications. By taking advantage of the modular organization of PRC2, we direct de novo recruitment of H3K9me3 and H3K36me3 to PRC2 target genes in H3K27me3 null mouse embryonic stem cells (mESCs). We show that despite accurate genome-wide re-establishment of H3K36me3 at PRC2 target genes, which leads to significant reduction in H3K4me3 levels, the remaining H3K4me3 prevents H3K36me3 from recruiting sufficient DNA methylation to substitute for H3K27me3-mediated repression. In contrast, we demonstrate that H3K9me3 is more efficient in repressing H3K27me3 regulated genes, however this repression is also contingent on H3K4me3 status. Taken together, these results highlight the unique repressive functions of H3K27me3 and suggest that the functional effects of individual posttranslational modifications are highly dependent on the interplay with the existing chromatin environment.
    DOI:  https://doi.org/10.1038/s41467-025-66426-z
  7. Cell Rep. 2025 Nov 26. pii: S2211-1247(25)01405-6. [Epub ahead of print]44(12): 116633
    FoxP3 forms a head-to-head dimer in vivo and stabilizes its multimerization on adjacent microsatellites.
    Fangwei Leng, Ryan Clark, Wenxiang Zhang, Thibault Viennet, Cuidie Wang, Haribabu Arthanari, Xi Wang, Sun Hur.
      FoxP3, the master regulator of Tregs, employs two DNA-binding modes to recognize diverse DNA sequences. It multimerizes on long TnG repeats (n = 2-5) to bridge DNA segments and stabilize chromatin loops, and it forms head-to-head (H-H) dimers on inverted repeat forkhead motifs (IR-FKHM) without bridging DNA. Although genomic data confirm its multimeric role, in vivo evidence for H-H dimerization has been elusive. Here, unbiased pull-down sequencing uncovers a range of relaxed motifs that drive H-H dimerization, enabling systematic genome-wide analysis. We demonstrate that FoxP3 binds genomic DNA as both H-H dimers and multimers in Tregs, with H-H binding often seeding and stabilizing multimerization on adjacent TnG repeats-especially on shorter, suboptimal repeats. While multimerization is conserved across FoxP family members, H-H dimerization is unique to FoxP3 orthologs, conferred by its divergent accessory loop. This dual-mode strategy broadens FoxP3's sequence repertoire and enhances its architectural function in chromatin looping.
    Keywords:  CP: Molecular biology; FoxP3; Treg; chromatin loop; microsatellite; multimerization; regulatory T cells; simple tandem repeat; transcription factor
    DOI:  https://doi.org/10.1016/j.celrep.2025.116633
  8. Sci Adv. 2025 Nov 28. 11(48): eady5507
    CTCF-RNA interactions orchestrate cell-specific chromatin loop organization.
    Kimberly Lucero, Sungwook Han, Pin-Yao Huang, Xiang Qiu, Esteban O Mazzoni, Danny Reinberg.
      CCCTC-binding factor (CTCF) is essential for chromatin organization. CTCF interacts with endogenous RNAs, and deletion of its ZF1 RNA binding region (∆ZF1) disrupts chromatin loops in mouse embryonic stem cells (ESCs). However, the functional significance of CTCF-ZF1 RNA interactions during cell differentiation is unknown. Using an ESC-to-neural progenitor cell (NPC) differentiation model, we show that CTCF-ZF1 is crucial for maintaining cell type-specific chromatin loops. Expression of CTCF-∆ZF1 leads to disrupted loops and dysregulation of genes within these loops, particularly those involved in neuronal development and function. We identified NPC-specific, CTCF-ZF1 interacting RNAs. Truncation of two such coding RNAs, Podxl and Grb10, disrupted chromatin loops in cis, similar to the disruption seen in CTCF-∆ZF1-expressing NPCs. These findings underscore the inherent importance of CTCF-ZF1 RNA interactions in preserving cell-specific genome structure and cellular identity.
    DOI:  https://doi.org/10.1126/sciadv.ady5507
  9. Sci Adv. 2025 Nov 28. 11(48): eadt6316
    Widespread association of Polycomb complex-deposited histone H2A monoubiquitylation with enhancers and neuronal gene regulation.
    Kailynn MacGillivray, Daniel Fusca, Luomeng Tan, Reta Aram, Arneet L Saltzman.
      Disruption of histone H2A monoubiquitylation (H2AK119ub) causes neurodevelopmental disorders through poorly understood mechanisms. Polycomb complex-deposited H2AK119ub and trimethylation of histone H3 at lysine 27 (H3K27me3) can cooperatively maintain gene repression. However, the extent to which H2AK119ub functions independently of H3K27me3 to repress or potentiate gene expression, and the evolutionary conservation of these roles, remains unclear. Here, we address the interplay among Polycomb-deposited marks and chromatin states in Caenorhabditis elegans embryos. We find that H2AK119ub distribution is distinct from and largely dispensable for H3K27me3 patterns. Unexpectedly, H2AK119ub is enriched at predicted enhancers with developmentally dynamic changes in accessibility, including in neurons. More than two-thirds of well-documented axon guidance genes and neuronal identity transcription factors are associated with H2AK119ub. Many of the genes differentially expressed in H2AK119ub-deficient animals are involved in neuronal differentiation and signaling and feature H2AK119ub-enriched promoters and enhancers, including a subset that is H3K27me3 repressed. We uncover a likely conserved yet underappreciated dual role for H2AK119ub at enhancers and H3K27me3-repressed chromatin, with implications for nervous system development.
    DOI:  https://doi.org/10.1126/sciadv.adt6316
  10. Nat Commun. 2025 Nov 27. 16(1): 10672
    Roles of histone chaperone Nap1 and histone acetylation in regulating phase-separation of nucleosome arrays.
    Jia Gao, Hongyun Li, Song Tan, Ruobo Zhou, Tae-Hee Lee.
      Chromatin condensation is dynamically regulated throughout the cell cycle and plays key roles in modulating gene accessibility. The DNA-histone dynamics in the nucleosome are central to the regulation mechanisms of chromatin condensation, which remain poorly understood. Employing fluorescence recovery after photobleaching, optical super-resolution imaging, and microrheology with optical tweezers, we investigated the roles of various parameters in regulating phase-separation of 12-mer nucleosome arrays. Here, we show that histone H4 tail lysine residues are the main drivers of liquid-liquid phase separation of nucleosome arrays. We also show that the condensed liquid-like droplets comprise a mobile fraction and a relatively immobile structural scaffold. Histone chaperone Nap1 and histone H3 tail acetylation enhance DNA-histone dynamics within this scaffold, thereby lowering the overall viscosity of the droplets. These results suggest that histone chaperone and histone H3/H4 tails play critical roles in regulating chromatin condensation and gene accessibility in condensed chromatin.
    DOI:  https://doi.org/10.1038/s41467-025-65701-3
  11. Nat Commun. 2025 Nov 26.
    H3K4me2 orchestrates H2A.Z and Polycomb repressive marks in Arabidopsis.
    Takumi Noyori, Shusei Mori, Satoyo Oya, Haruki Nishio, Hiroshi Kudoh, Soichi Inagaki, Tetsuji Kakutani.
      The dimethylation of histone H3 lysine 4 (H3K4me2) plays an important role in developmental phase transitions in plants, such as regeneration from the callus and the initiation of flowering. H3K4me2 in plants is correlated with transcriptionally repressed states, which can be accounted for by transcription-coupled active H3K4me2 demethylation, but the converse molecular pathway by which H3K4me2 represses transcription remains largely unexplored. Here, we show that H3K4me2 colocalizes with the H2A variant H2A.Z and H2A ubiquitination (H2Aub). Our genetic analyses reveal that H3K4me2 functions upstream but not downstream of these marks. H3K4me2 also partially colocalizes with the facultative heterochromatin mark H3K27me3, and loss of H3K4me2 causes a decrease in the colocalized H3K27me3. Interestingly, in genes with diel H3K4me2 oscillation, H3K4me2 oscillates in antiphase with transcription but in phase with H2A.Z. In addition, the genetic manipulation of H3K4me2 affects the oscillating profiles of H2A.Z, suggesting the efficient relay from H3K4me2 to H2A.Z. Notably, the diel oscillation of H2Aub is much weaker than that of H2A.Z despite the overall similarity in their distributions. These results suggest that H3K4me2 orchestrates H2A.Z and H2Aub with distinct dynamics. We propose that H3K4me2 promotes stepwise progression of chromatin toward repressive states in plants.
    DOI:  https://doi.org/10.1038/s41467-025-66645-4
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