bims-crepig 2026-01-11 papers

bims-crepig

Biomed News

on Chromatin regulation and epigenetics in cell fate and cancer

Issue of 2026–01–11
eleven papers selected by
Connor Rogerson, University of Cambridge

Basis for lineage-determining pioneer factors targeting distinct repressed chromatin states.
Short activation domains control chromatin association of transcription factors.
A SET domain-containing protein and HCF-1 maintain transgenerational epigenetic memory.
Cell-cycle-dependent repression of histone gene transcription by histone H4.
YAP-TEAD regulates the super-enhancer network to control early surface ectoderm commitment.
Bacterial chromatin remodeling associated with transcription-induced domains at pathogenicity Islands.
Chromatin folding principles underlying the generation of antibody diversity.
An expanded registry of candidate cis-regulatory elements.
Multimodal epigenetic and enhancer network remodeling shape the transcriptional landscape of human beige adipocytes.
Multimodal bHLH-PAS DNA binding controls specificity and drives obesity.
DNA actively regulates the "safety-belt" dynamics of condensin during loop extrusion.

Sci Adv. 2026 Jan 09. 12(2): eadz7409

Basis for lineage-determining pioneer factors targeting distinct repressed chromatin states.

Andrew Katznelson, Jingchao Zhang, Greg Donahue, Kenneth S Zaret.

Pioneer transcription factors target transcriptionally silent chromatin, thereby enabling gene activation in development, regeneration, and cell reprogramming. However, silent chromatin is heterogeneous, varying in nucleosome stability, nucleosome compaction, and repressive histone modifications, and how pioneer factors may differentially overcome these different chromatin barriers is unknown. We systematically compared the chromatin targeting of 13 embryonic transcription factors and found that the DNA binding domain (DBD) type predicts whether a pioneer factor targets low-turnover nucleosomes in compact chromatin, dynamic nucleosomes in compact chromatin or functions as a nonpioneer factor targeting accessible chromatin. By contrast, non-DBD domains enable targeting of repressed chromatin marked by H3K9me3 or H3K27me3. Fusions of different non-DBD segments of heterochromatin-targeting pioneer factors to the transcription factor SOX2 can expand binding of SOX2 target motifs within heterochromatin and improve cellular reprogramming. Our study unveils how different forms of silent chromatin are coordinately targeted by lineage-specifying factors.

DOI: https://doi.org/10.1126/sciadv.adz7409
Elife. 2026 Jan 09. pii: e105776. [Epub ahead of print]15

Short activation domains control chromatin association of transcription factors.

Vinson B Fan, Abrar A Abidi, Thomas G W Graham, Xavier Darzacq, Max V Staller.

  Transcription factors regulate gene expression with DNA-binding domains (DBDs) and activation domains. Despite evidence to the contrary, DBDs are often assumed to be the primary mediators of transcription factor (TF) interactions with DNA and chromatin. Here, we used fast single-molecule tracking of transcription factors in living cells to show that short activation domains can control the fraction of molecules bound to chromatin. Stronger activation domains have higher bound fractions and longer residence times on chromatin. Furthermore, mutations that increase activation domain strength also increase chromatin binding. This trend was consistent in four different activation domains and their mutants. This effect further held for activation domains appended to three different structural classes of DBDs. Stronger activation domains with high chromatin-bound fractions also exhibited increased binding to the p300 coactivator in proximity-assisted photoactivation experiments. Genome-wide measurements indicate these activation domains primarily control the occupancy of binding rather than the genomic location. Taken together, these results demonstrate that very short activation domains play a major role in tethering transcription factors to chromatin.

Keywords:  activation domain; chromosomes; gene expression; human; molecular biophysics; single-molecule imaging; structural biology; transcription; transcription factor

DOI:  https://doi.org/10.7554/eLife.105776
Nat Commun. 2026 Jan 09.

A SET domain-containing protein and HCF-1 maintain transgenerational epigenetic memory.

Chenming Zeng, Giulia Furlan, Miguel Vasconcelos Almeida, Juan C Rueda-Silva, Jonathan Price, Helena Santos-Rosa, Jingxiu Xu, Yan Kuang, Enric Cata Socias, Jonas Mars, Pedro Rebelo-Guiomar, Meng Huang, Shouhong Guang, Falk Butter, Eric A Miska.

Transgenerational epigenetic inheritance (TEI) allows epigenetic information to pass across generations through mechanisms such as small RNAs and histone modifications. Histone methylation is often deposited by SET domain-containing methyltransferases. Some SET proteins lack catalytic activity but still regulate chromatin and gene expression. Here, we characterize SET-24, a catalytically inactive SET domain protein that localizes to germline nuclei and is essential for germline immortality in Caenorhabditis elegans. In set-24 mutants, small RNA-mediated epigenetic silencing is impaired. Proteomic, yeast two-hybrid, and pull-down assays show that SET-24 interacts with HCF-1, a chromatin factor linked to complexes like COMPASS, which deposits H3K4me3. Loss of SET-24 leads to increased H3K4me3 at transcription start sites of hundreds of genes. Although transcription remains largely unchanged, small RNA production is disrupted for about 30% of these genes. We propose that SET-24 preserves germline epigenetic memory by sustaining a chromatin environment that supports small RNA biogenesis across generations.

DOI: https://doi.org/10.1038/s41467-025-68200-7
Nat Struct Mol Biol. 2026 Jan 05.

Cell-cycle-dependent repression of histone gene transcription by histone H4.

Kami Ahmad, Matt Wooten, Brittany N Takushi, Velinda Vidaurre, Xin Chen, Steven Henikoff.

In all eukaryotes, DNA replication is coupled to histone synthesis to coordinate chromatin packaging of the genome. Canonical histone genes coalesce in the nucleus into the histone locus body (HLB), where gene transcription and 3' mRNA processing occurs. Both histone gene transcription and mRNA stability are reduced when DNA replication is inhibited, implying that the HLB senses the rate of DNA synthesis. In Drosophila melanogaster, the S-phase-induced histone genes are tandemly repeated in an ~100 copy array, whereas, in humans, these histone genes are scattered. In both organisms, these genes coalesce into HLBs. Here, we use a transgenic histone gene reporter and RNA interference in Drosophila to identify canonical H4 histone as a unique repressor of histone synthesis during the G2 phase in germline cells. Using cytology and CUT&Tag chromatin profiling, we find that histone H4 uniquely occupies histone gene promoters in both Drosophila and human cells. Our results suggest that repression of histone genes by soluble histone H4 is a conserved mechanism that coordinates DNA replication with histone synthesis in proliferating cells.

DOI: https://doi.org/10.1038/s41594-025-01731-1
Nucleic Acids Res. 2026 Jan 05. pii: gkaf1285. [Epub ahead of print]54(1):

YAP-TEAD regulates the super-enhancer network to control early surface ectoderm commitment.

Zhiming Wang, Chen Yang, Ziyue Ma, Xiaoyu He, Linying Li, Yihao Wang, Yexin Wang, Xiaodong Cai, Huiyuan Jiao, Mengqi Zhang, Ran Tong, Feng Zhang, Lingjie Li.

Super enhancers (SEs), characterized by clusters of enhancers, are instrumental in shaping cellular identity and function. Given this crucial involvement of SEs in cell lineage commitment, and considering the pivotal position of surface ectoderm in differentiating into a wide array of cell types, the study of these SEs holds immense promise for advancing cell-based therapeutic applications. In this study, we profiled the SE landscape in surface ectoderm cells derived from pluripotent stem cell differentiation. By leveraging 3D genomic data, we discerned active histone modifications and frequent chromatin interactions of SEs with target genes. Notably, perturbing specific SE using a CRISPR-dCas9-mediated approach resulted in decreased expression of the connected gene. Subsequently, we constructed a regulatory network of core transcription factors (TFs) operating on SEs and uncovered their control over the differentiation process by forming regulatory network with key TFs, such as TEAD1. Knocking down TEADs attenuated the differentiation process and target gene activation, whereas YAP-TEAD activation expedited the differentiation process by promoting the early establishment of SEs. Collectively, our findings shed light on the crucial role of SEs and identify YAP-TEAD as vital regulators controlling surface ectoderm commitment, thereby providing a novel insight into lineage commitment and stem cell-based epithelial regeneration.

DOI: https://doi.org/10.1093/nar/gkaf1285
Nat Commun. 2026 Jan 08. 17(1): 161

Bacterial chromatin remodeling associated with transcription-induced domains at pathogenicity Islands.

Mounia Kortebi, Mickaël Bourge, Romain Le Bars, Erwin Van Dijk, Charles J Dorman, Stéphanie Bury-Moné, Frédéric Boccard, Virginia S Lioy.

The nucleoid-associated protein H-NS is a bacterial xenogeneic silencer responsible for preventing costly expression of genes acquired through horizontal gene transfer. H-NS silences several Salmonella Pathogenicity Islands (SPIs) essential for host infection. The stochastic expression of SPI-1 is required for invasion of host epithelial cells but complicates investigation of factors involved in SPI-1 chromatin structure and regulation. We performed functional genomics on sorted Salmonella populations expressing SPI-1 or not, to characterize how SPI-1 activation affects chromatin composition, DNA conformation, gene expression and SPI-1 subcellular localization. We show that silent SPIs are associated with spurious antisense transcriptional activity originating from H-NS-free regions. Upon SPI-1 activation, remodeling of H-NS occupancy defines a new chromatin landscape, which together with the master SPI-1 regulator HilD, facilitates transcription of SPI-1 genes. SPI-1 activation promotes formation of Transcription Induced Domains accompanied by repositioning SPI-1 close to the nucleoid periphery. We present a model for tightly regulated chromatin remodeling that minimizes the cost of pathogenicity island activation.

DOI: https://doi.org/10.1038/s41467-025-67746-w
Mol Cell. 2026 Jan 08. pii: S1097-2765(25)01022-6. [Epub ahead of print]

Chromatin folding principles underlying the generation of antibody diversity.

Noah Ollikainen, Fei Ma, Fatima Zohra Braikia, Ranjan Sen.

  Effective adaptive immunity requires generation of a diverse repertoire of antigen receptors via V(D)J recombination. To illuminate the underlying mechanisms, we combined biophysical simulations with experimental data to model chromatin folding and dynamics of the mouse immunoglobulin heavy chain gene (Igh) locus. Simulations that best recapitulated experimental data on locus structure and recombination of Igh alleles identified three novel chromatin folding principles. First, we found that prominent structural features of the Igh locus, such as the 3'-anchored stripe, required cohesin loading throughout the locus. Second, the Eμ enhancer was best modeled as a bi-directional loop extrusion blocker, though it does not bind CTCF. Third, we found that utilization of VH genes to obtain maximum diversity required both widespread cohesin loading as well as long-range associations between H3K27ac-marked regions. Our findings provide a conceptual framework to understand chromatin folding principles that enable antibody diversity and reveal mechanisms of long-range genome communication.

Keywords:  3D genome organization; V(DJ) recombination; adaptive immunity; antibody diversity; biophysical simulations; chromatin folding; chromatin loop extrusion; chromatin structure; enhancer function; immune repertoire regulation; immunoglobulin heavy chain locus; long-range genomic interactions

DOI:  https://doi.org/10.1016/j.molcel.2025.12.023
Nature. 2026 Jan 07.

An expanded registry of candidate cis-regulatory elements.

Jill E Moore, Henry E Pratt, Kaili Fan, Nishigandha Phalke, Jonathan Fisher, Shaimae I Elhajjajy, Gregory Andrews, Mingshi Gao, Nicole Shedd, Yu Fu, Matthew C Lacadie, Jair Meza, Mansi Khandpekar, Mohit Ganna, Eva Choudhury, Ross Swofford, Huong Phan, Christian C Ramirez, Maxwell Campbell, Mary Likhite, Nina P Farrell, Annika K Weimer, Anusri Pampari, Vivekanandan Ramalingam, Fairlie Reese, Beatrice Borsari, Xuezhu Yu, Eve Wattenberg, Marina Ruiz-Romero, Milad Razavi-Mohseni, Jinrui Xu, Timur Galeev, Andres Colubri, Michael A Beer, Roderic Guigó, Mark B Gerstein, Jesse M Engreitz, Mats Ljungman, Timothy E Reddy, Michael P Snyder, Charles B Epstein, Elizabeth Gaskell, Bradley E Bernstein, Diane E Dickel, Axel Visel, Len A Pennacchio, Ali Mortazavi, Anshul Kundaje, Zhiping Weng.

Mammalian genomes contain millions of regulatory elements that control the complex patterns of gene expression1. Previously, the ENCODE consortium mapped biochemical signals across hundreds of cell types and tissues and integrated these data to develop a registry containing 0.9 million human and 300,000 mouse candidate cis-regulatory elements (cCREs) annotated with potential functions2. Here we have expanded the registry to include 2.37 million human and 967,000 mouse cCREs, leveraging new ENCODE datasets and enhanced computational methods. This expanded registry covers hundreds of unique cell and tissue types, providing a comprehensive understanding of gene regulation. Functional characterization data from assays such as STARR-seq3, massively parallel reporter assay4, CRISPR perturbation5,6 and transgenic mouse assays7 have profiled more than 90% of human cCREs, revealing complex regulatory functions. We identified thousands of novel silencer cCREs and demonstrated their dual enhancer and silencer roles in different cellular contexts. Integrating the registry with other ENCODE annotations facilitates genetic variation interpretation and trait-associated gene identification, exemplified by the identification of KLF1 as a novel causal gene for red blood cell traits. This expanded registry is a valuable resource for studying the regulatory genome and its impact on health and disease.

DOI: https://doi.org/10.1038/s41586-025-09909-9
Commun Biol. 2026 Jan 08.

Multimodal epigenetic and enhancer network remodeling shape the transcriptional landscape of human beige adipocytes.

Sarah Hazell Pickering, Natalia M Galigniana, Mohamed Abdelhalim, Anita L Sørensen, Julia Madsen-Østerbye, Manuela Zucknick, Philippe Collas, Nolwenn Briand.

Epigenetic regulation is a key determinant of adipocyte fate, driving the differentiation toward white or thermogenic beige phenotypes in response to environmental cues. To dissect the mechanisms orchestrating this plasticity in human adipocytes, we conducted an integrative analysis of transcriptomic, epigenomic and enhancer connectome dynamics throughout white and beige adipogenesis. Using a machine learning approach, we show that the white transcriptional program is tightly linked to promoter-level modulation of H3K27ac and chromatin accessibility, whereas the beige-specific induction of mitochondrial genes is driven by promoter remodeling of H3K4me3, underscoring distinct epigenetic mechanisms for white or beige specification. Adipocyte beiging is accompanied by a targeted reorganization of the 3D genome, characterized by increased recruitment of short-range enhancers controlling thermogenesis genes, enriched for C/EBP transcription factor binding sites. Our findings highlight the multimodal regulation of the beige adipocyte fate, driven by the interplay of chromatin state transitions, enhancer rewiring, and transcription factor dynamics.

DOI: https://doi.org/10.1038/s42003-025-09469-8
Nucleic Acids Res. 2026 Jan 05. pii: gkaf1352. [Epub ahead of print]54(1):

Multimodal bHLH-PAS DNA binding controls specificity and drives obesity.

David C Bersten, Daniel P McDougal, Adrienne E Sullivan, Alexis Gerassimou, James Breen, Rebecca L Fitzsimmons, George E O Muscat, Stephen Pederson, John B Bruning, Chen-Ming Fan, Paul Q Thomas, Darryl L Russell, Daniel J Peet, Murray L Whitelaw.

The basic-helix-loop-helix Per-Arnt-Sim (PAS) homology domain (bHLH-PAS) transcription factor (TF) family comprises critical sensors or actuators of physiological (hypoxia, tryptophan metabolites, neuronal activity, and appetite) and environmental (diet-derived metabolites and pollutants) stimuli regulating genes involved in signal adaptation and homeostasis. Despite the importance of this TF family, the mechanisms underlying specificity of DNA binding and target gene regulation by the bHLH-PAS subfamily remain unresolved. We systematically analysed cognate DNA binding hierarchies of prototypical bHLH-PAS family members (ARNT, ARNT2, HIF1α, HIF2α, AhR, NPAS4, SIM1), revealing large DNA binding footprints (12-15 bp) and unique mechanisms of DNA binding specificity involving preferential DNA sequences flanking the core motif. Flank-encoded DNA binding specificity discerns otherwise identical core sequence binding by SIM1 and the HIFs, mediated through N-terminal HIFα-DNA interactions. We also reveal an intimate relationship between DNA shape and core and flank TF binding that allows motif sequence flexibility and underpins multimodal mechanisms for achieving TF binding specificity. Furthermore, novel downstream SIM1 PAS-loop/DNA interactions are associated with AT-rich sequences contributing to DNA binding and transcriptional activity; these interactions are critical for TF biological function underpinning a monogenic cause of human hyperphagic obesity in a recapitulated SIM1.R171H knock-in mouse model.

DOI: https://doi.org/10.1093/nar/gkaf1352
Nat Commun. 2026 Jan 07.

DNA actively regulates the "safety-belt" dynamics of condensin during loop extrusion.

Jinyu Chen, Cibo Feng, Yong Wang, Xiakun Chu.

Condensin plays an essential role in genome folding through its active DNA loop extrusion activity. Condensin contains a binding interface between its Ycg1 HEAT-repeat subunit and the Brn1 kleisin, together forming a "safety-belt" DNA-binding groove. This safety-belt architecture traps DNA inside the structural maintenance of chromosomes complex and prevents its dissociation during loop extrusion. The entrapment of DNA within the binding pocket of the complex is crucial for ATPase activity and loop extrusion. However, the molecular mechanism underlying DNA entrapment remains unclear. Here, we employ a multiscale computational approach to understand how DNA modulates yeast condensin's safety-belt dynamics. Using all-atom simulations combined with AlphaFold3 predictions, we demonstrate that DNA binding stabilizes the Ycg1-Brn1 safety belt. Coarse-grained simulations capture the entire DNA-entrapment process and reveal an active regulatory role for DNA: outside the safety belt, DNA triggers opening, whereas once inside, it promotes closure and stabilizes the complex. Kinetic analyses show that the rate-limiting step in DNA entrapment depends on the tightness of the safety belt. A loose safety belt makes the stable closure of its "latch" and "buckle" components rate-limiting, whereas a tighter safety belt shifts the barrier to initial DNA entry.

DOI: https://doi.org/10.1038/s41467-025-68239-6