bims-crepig Biomed News
on Chromatin regulation and epigenetics in cell fate and cancer
Issue of 2026–02–15
fourteen papers selected by
Connor Rogerson, University of Cambridge
  1. Sequencing DNA methylation and hydroxymethylation at co-occurring chromatin features.
  2. Electrostatic properties of disordered regions control transcription factor search and pioneer activity.
  3. The human BAF chromatin remodeler processes nucleosomes bound by pioneer transcription factors OCT4-SOX2.
  4. An upstream secondary DNA motif within the IL3 insulator CTCF binding site is required for enhancer-blocking insulator activity.
  5. Scaffolding of the H4K5ac chromatin remodeling complex by lncRNA MAHAC mediates epithelial-mesenchymal transition.
  6. Distinct roles for SETα and SETβ in early cell fate decisions.
  7. Chromatin binding and N-terminal domains of DNMT3B1 confer specificity for developmentally regulated CpG island methylation.
  8. Enhancer dynamics and cellular architecture in the human spinal cord.
  9. Human CRAMP1 specifically promotes the expression of histone H1 genes.
  10. Unbalanced chromatin binding of Polycomb complexes drives neurodevelopmental disorders.
  11. dHyperCas12a enables multiplexed CRISPRi screens.
  12. Dissecting reversible and irreversible single cell state transitions from gene regulatory networks.
  13. Histone H3 tail charge patterns govern nucleosome condensate formation and dynamics.
  14. Transcription factor Etv3 controls the tolerogenic function of dendritic cells.
  1. Nat Commun. 2026 Feb 10.
    Sequencing DNA methylation and hydroxymethylation at co-occurring chromatin features.
    Rafael de Cesaris Araujo Tavares, Somdutta Dhir, Xuan He, Jack Monahan, Minna Taipale, Paula Golder, Aldo Ciau-Uitz, Walraj Gosal, David Tannahill, Shankar Balasubramanian.
      Epigenetic modifications govern chromatin dynamics and cell state. However, current methods cannot simultaneously resolve the presence of multiple DNA modifications at co-occurring chromatin-associated features. It is thus not clear how these features are physically coupled and how their combinations regulate genome function. To address this key question, we report 6-base-CUT&Tag, a method for simultaneous 6-base DNA sequencing at target chromatin features. Using 6-base-CUT&Tag to profile 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) at co-occurring histone modifications in mouse embryonic stem cells (mESCs), we identify feature-dependent 5mC/5hmC signatures previously unresolvable with untargeted or bisulfite-based workflows. We show that DNA methylation and hydroxymethylation are specifically coupled with the H3K4me1 mark in mESC enhancers and that H3K4me1-derived signatures robustly distinguish different enhancer functional states.
    DOI:  https://doi.org/10.1038/s41467-026-69429-6
  2. Nat Commun. 2026 Feb 08.
    Electrostatic properties of disordered regions control transcription factor search and pioneer activity.
    Sim Sakong, Beat Fierz, David M Suter.
      Transcription factors (TFs) search for and bind specific DNA target sites to control gene expression. However, eukaryotic TF target search within the chromatinized genome is poorly characterized. Here, we combine in vivo and in vitro single-molecule imaging to dissect the role of differentially-charged DNA-binding domain flanking regions in the target search of Sox TFs. We demonstrate that the flanking region of Sox2 markedly enhances search efficiency compared to the negatively-charged flanking region of Sox17. The involved mechanisms are distinct for naked DNA compared to chromatin. On DNA, the enhanced search of Sox2 is driven by an increased target recognition rate during 1D sliding, despite reduced sliding speed. Conversely, enhanced nonspecific interactions between the Sox2's DNA-binding domain flanking region and nucleosomes facilitate binding to compact chromatin and reinforce pioneer activity. These findings provide critical insights into biophysical mechanisms governing TF target search within the chromatinized genome.
    DOI:  https://doi.org/10.1038/s41467-026-69284-5
  3. Mol Cell. 2026 Feb 11. pii: S1097-2765(26)00063-8. [Epub ahead of print]
    The human BAF chromatin remodeler processes nucleosomes bound by pioneer transcription factors OCT4-SOX2.
    Joscha Weiss, Luca Vecchia, David Domjan, Simone Cavadini, Anton Sabantsev, Georg Kempf, Ganesh R Pathare, Klaus Brackmann, Alicia K Michael, Lukas Kater, Eric Hietter-Pfeiffer, Mina Haddawi, Urja P Kuber, Sandra Mühlhäusser, Ralph S Grand, Michael B Stadler, Sebastian Deindl, Nicolas H Thomä.
      Chromatin remodeling complexes mobilize nucleosomes and promote transcription factor (TF) binding. Using ensemble and single-molecule assays combined with cryo-electron microscopy (cryo-EM), we studied the interaction between pioneer TFs OCT4-SOX2 and the human BRG1/BRM-associated factor (BAF) complex on nucleosomes. BAF engages TF-bound substrates in two orientations, placing OCT4-SOX2 at either the remodeler ENTRY or EXIT site. At the ENTRY site, OCT4-SOX2 initially coexists with BAF without structural interference. However, continued DNA translocation is expected to cause collisions with bound TFs, which can trigger remodeling direction reversals or may induce TF dissociation. To accommodate TFs at the EXIT site, BAF undergoes structural rearrangements, and ensemble assays reveal a nucleosome subpopulation translocating away from TF-binding sites. Moreover, single-molecule experiments show that nucleosome-bound BAF frequently changes remodeling direction, and we identify an ADP-bound remodeler conformation as a potential intermediate. Together, these findings reveal key aspects of the conformational dynamics and remodeling outcomes underlying BAF processing of TF-bound nucleosomes.
    Keywords:  BAF; OCT4; SOX2; SWI/SNF; chromatin remodelers; cryo-EM; gene regulation; nucleosome; pioneer TFs; single-molecule FRET
    DOI:  https://doi.org/10.1016/j.molcel.2026.01.021
  4. PLoS One. 2026 ;21(2): e0340247
    An upstream secondary DNA motif within the IL3 insulator CTCF binding site is required for enhancer-blocking insulator activity.
    Sarion R Bowers, Peter N Cockerill.
      CCCTC-binding Factor (CTCF) is the only known vertebrate protein that functions to organise the genome into distinct functional chromatin domains. A subset of CTCF sites also provide insulator activity and barrier activity to block inappropriate enhancer-promoter communication and spreading of histone modifications and non-coding transcription into loci where it is unwarranted. Paradoxically, other CTCF sites mediate enhancer and promoter communication, partly by supporting DNA loop extrusion within chromatin domains. Despite intensive study and abundant data, it remains poorly understood how CTCF directs these different functions. In this study we provide new data and mine published data that show that CTCF utilises zinc fingers 9-11 and an upstream DNA binding consensus sequence resembling CAGCTGTTCC to mediate high affinity binding and enhancer-blocking insulator activity. A single high affinity CTCF binding site from the IL3 locus is able block IL3 promoter activation by an upstream enhancer. Mutation of a CTGCAGCTTT sequence upstream of the CTCF core motif abolishes insulator activity. We propose that CTCF is able to confer insulator and barrier activity upon a specific subset of CTCF sites that contain the upstream DNA consensus binding motif, thereby allowing CTCF to function differently in different contexts.
    DOI:  https://doi.org/10.1371/journal.pone.0340247
  5. Nucleic Acids Res. 2026 Feb 05. pii: gkag101. [Epub ahead of print]54(4):
    Scaffolding of the H4K5ac chromatin remodeling complex by lncRNA MAHAC mediates epithelial-mesenchymal transition.
    Kai-Wen Hsu, Jeng-Shou Chang, Joseph Chieh-Yu Lai, Li-Hao Yang, Pei-Hua Peng, Tzu-Chin Lin, Kou-Juey Wu.
      Anchoring of a chromatin remodeler complex by long non-coding RNAs (lncRNAs) is a frequently utilized mechanism for lncRNAs to regulate gene expression. Hypoxia is a microenvironmental condition that plays a crucial role in promoting tumor progression. We previously identified a hypoxia-inducible lncRNA, RP11-390F4.3, that regulates epithelial-mesenchymal transition (EMT) without a delineated mechanism. Here, we show that the lncRNA RP11-390F4.3 (renamed MAHAC: MAintenance of Histone ACetylation) specifically induces histone H4 lysine 5 acetylation (H4K5ac) mark and promotes the deposition of H4K5ac mark on the promoters of EMT transcription factors. MAHAC scaffolds the ILF3/NF90-ILF2-CBP complex, which is co-localized with the members of the complex inside the nucleus under hypoxia. The minimal MAHAC region (nt 686-741) required for scaffolding the complex was mapped, and it induces allosteric activation of H4K5ac in in vitro histone acetyltransferase assay. This minimal MAHAC region is essential for hypoxia-induced EMT, migration, invasion, and H4K5ac activation. These findings demonstrate that hypoxia-induced MAHAC represents an unexplored allosteric regulator of H4K5ac that activates EMT and induces tumor progression.
    DOI:  https://doi.org/10.1093/nar/gkag101
  6. Nucleic Acids Res. 2026 Feb 05. pii: gkag105. [Epub ahead of print]54(4):
    Distinct roles for SETα and SETβ in early cell fate decisions.
    Patrick Siang Lin Lim, Eden Mishne, Malka Nissim-Rafinia, Eran Meshorer.
      SET, the nuclear proto-oncogene, is primarily expressed as SETα in embryonic stem cells (ESCs). Upon pluripotency exit, a transcriptional switch driven by alternative promoters causes SETβ to largely replace SETα expression. Functional distinctions between the two isoforms have been difficult to ascertain, partly due to the redundancy between SETα and SETβ in their protein structure and activity. In this study, we use ESCs with inducible SET isoform-specific expression to investigate the differences between both SET isoforms. Time-course RNA-sequencing analyses in SET-knockout backgrounds as well as isoform-specific chromatin immunoprecipitation followed by sequencing experiments reveal regulatory functions for SETα and SETβ. Despite sharing many binding sites and binding partners, SETα has unique regulatory functions on its target genes, while SETβ downregulates FGF4. As KLF5 specifically regulates SETα, this implicates SET isoform switching at the KLF5/FGF signalling axis during primitive endoderm specification. Together, we propose a model of how distinct roles of SETα and SETβ may regulate cell identity in the early blastocyst.
    DOI:  https://doi.org/10.1093/nar/gkag105
  7. Genes Dev. 2026 Feb 11.
    Chromatin binding and N-terminal domains of DNMT3B1 confer specificity for developmentally regulated CpG island methylation.
    Komal Yasmin, Tatyana B Nesterova, Neil Brockdorff.
      CpG methylation in mammalian genomes is established by the closely related de novo DNA methyltransferases DNMT3A and DNMT3B. While both enzymes contribute to genome-wide CpG methylation, DNMT3B has a unique role in developmentally regulated CpG island (CGI) methylation on the inactive X chromosome and at other sites in the genome. The mechanistic basis for this specificity is poorly understood. Here we have developed an in vitro embryonic stem cell model system to dissect critical determinants of DNMT3B specificity. Our model faithfully recapitulates developmentally regulated CGI methylation and additionally provides novel insights into CpG methylation at cis-regulatory elements. Using genetic complementation, we show that DNMT3B specificity is attributable solely to the major catalytic isoform DNMT3B1. Domain swap experiments demonstrate a role for the PWWP-ADD chromatin binding domains, while deletion analysis reveals the importance of the unstructured N-terminal domain, including a requirement for a specific subregion in CGI methylation on Xi. Together, these findings advance our mechanistic understanding of the unique roles of DNMT3 enzymes in establishing CpG methylation in development.
    Keywords:  CpG island; DNA methylation; X inactivation; chromatin; epigenetics
    DOI:  https://doi.org/10.1101/gad.353014.125
  8. Neuron. 2026 Feb 12. pii: S0896-6273(25)00991-2. [Epub ahead of print]
    Enhancer dynamics and cellular architecture in the human spinal cord.
    Elena K Kandror, Mathieu Carriere, Alexis Peterson, Will Liao, Andreas Tjärnberg, Jun Hou Fung, Krishnaa T Mahbubani, Jackson Loper, William Pangburn, Yuchen Xu, Kourosh Saeb-Parsy, Tom Maniatis, Abbas H Rizvi.
      Studies of neurodegenerative disease mechanisms require an understanding of the cellular complexity of the healthy human spinal cord. Here, we report the spatial organization of RNA transcription and associated enhancer dynamics in the adult human spinal cord at single-cell and single-molecule resolution. We expand traditional multi-omic measurements and identify epigenetically poised and bivalent active transcriptional enhancer states that define cell-type specification. Simultaneous detection of chromatin accessibility and histone modifications in spinal cord nuclei reveals previously unobserved cell-type-specific masked enhancer activity, in which transcriptional activation is uncoupled from chromatin accessibility. Such masked enhancers define both stable cell-type identity and transitions between cells undergoing differentiation. We also define gene regulatory networks in glial cells that reorganize along the rostrocaudal axis, demonstrating anatomical differences in gene regulation. Finally, we identify the spatial organization of cells into distinct cellular networks and address the functional significance of this observation in the context of paracrine signaling. We conclude that cellular diversity in the spinal cord is best captured through the lens of enhancer state and intercellular interactions that drive transitions in cellular state.
    Keywords:  computational biology; enhancer dynamics; gene regulation; multiomics; single-nucleus epigenomics; spatial transcriptomics; spinal cord
    DOI:  https://doi.org/10.1016/j.neuron.2025.12.035
  9. EMBO Rep. 2026 Feb 09.
    Human CRAMP1 specifically promotes the expression of histone H1 genes.
    Justin Bodner, Pranathi Vadlamani, Alexander S Lee, Kathryn A Helmin, Qianli Liu, Almira E Pratasenia, Maria M A Horst, Sudharsana Ravisankar, Sakshi Khurana, Marc L Mendillo, Benjamin D Singer, Shashank Srivastava, Daniel R Foltz.
      Proper histone gene expression is critical for cell viability and maintenance of genomic integrity. Multiple histone genes are organized into three genomic loci that encode replication-coupled core and linker histones. Histone gene expression and transcript processing are orchestrated in the histone locus body (HLB) within the nucleus. Here, we identify human CRAMP1 as a selective regulator of the linker histone H1 expression. Human CRAMP1 is recruited to the HLB in RPE1hTERT cells. Immunoprecipitation combined with mass spectrometry shows CRAMP1 physically associates with the HLB component GON4L (also known as YARP). We demonstrate that the PAH domains of GON4L interact with CRAMP1. CRAMP1 disruption results in reduced histone H1 mRNA expression and histone H1 protein levels, with no significant changes in core histone gene expression. CRAMP1 occupies the promoters of actively expressed replication-coupled linker histone genes that reside within the histone locus body and replication-independent histone H1 loci, which reside in a region of the genome without other histone genes. Together, these data identify CRAMP1 as a novel and selective regulator of histone H1 gene expression.
    Keywords:  Chromatin; Histone; Nucleosome; Nucleus; Transcription
    DOI:  https://doi.org/10.1038/s44319-026-00704-9
  10. Mol Cell. 2026 Feb 06. pii: S1097-2765(26)00065-1. [Epub ahead of print]
    Unbalanced chromatin binding of Polycomb complexes drives neurodevelopmental disorders.
    Rodrigo L Borges, Gretter González-Blanco, Harikumar Arigela, Yingyu Huang, Lucas D Caeiro, Nikolai Fattakhov, Stefano Lepore, Liliana Garcia-Martinez, Matea Maurice, Pushti D Mehta, Emily J Park, Kailynn MacGillivray, Jevithen Nehru, Matthew Chau, Maria C Robayo, Clemer Abad, Alicia Bilbao-Martinez, Fabiola Monteiro, Xi Luo, Song Tan, Daniel Bilbao, Simone Sidoli, Bruno Di Stefano, Katherina Walz, Arneet L Saltzman, Ramiro E Verdun, Ramin Shiekhattar, Lluis Morey.
      The prevalence of neurodevelopmental disorders (NDDs) in children is increasing, yet their underlying causes remain largely unknown. We identified heterozygous mutations in the Polycomb repressive complex 1 (PRC1) E3 ligases RING1 and RNF2 in individuals with NDDs and revealed distinct mechanisms by which they compromise PRC1 activity. We developed cellular and mouse models carrying the Ring1bR70H variant, which disrupts PRC1/PRC2 recruitment balance and mis-regulates Polycomb target genes. Allele-specific profiling showed that Ring1bR70H preferentially assembles into canonical PRC1 (cPRC1) via the intrinsically disordered region (IDR) of Pcgf2, reducing variant PRC1 (vPRC1) and PRC2.1 binding to chromatin. In Rnf2WT/R70H neuroprecursors, Polycomb complexes aberrantly suppress Wnt signaling, diverting neuroprecursors to non-neuronal lineages and halting neurogenesis. Rnf2R70H/R70H mice are perinatally lethal, while heterozygotes exhibit altered axonal organization, hippocampal and medial prefrontal cortex (mPFC) neuronal imbalances, reduced sociability, and increased anxiety. Our findings reveal an epigenetic mechanism essential for neurodevelopmental integrity and brain function and demonstrate how mutations in Rnf2 disrupt PRC1 occupancy at chromatin, contributing to NDDs.
    Keywords:  Polycomb; epigenetics; genetic variants; neurodevelopmental disorders; neurogenesis; stem cells
    DOI:  https://doi.org/10.1016/j.molcel.2026.01.023
  11. Nat Commun. 2026 Feb 12.
    dHyperCas12a enables multiplexed CRISPRi screens.
    Schuyler M Melore, Christian D McRoberts Amador, Marisa C Hamilton, Charles A Gersbach, Timothy E Reddy.
      Interactions between genes or cis-regulatory elements (CREs) underlie many biological processes. High-throughput CRISPR screens have allowed researchers to assess the impact of activation or repression of gene and regulatory elements on many phenotypes. However, assessment of interactions between those genes or elements remains limited. To enable efficient highly-multiplexed control of regulatory element activity, we combine a hyper-efficient version of Lachnospiraceae bacterium dCas12a (dHyperLbCas12a) with RNA Polymerase II expression of long CRISPR RNA (crRNA) arrays. We demonstrate this system with several activation and repression domains, in cultured primary immune cells, and to differentiate induced pluripotent stem cells. We also develop approaches to use dCas12a for simultaneous activation and repression. Lastly, we demonstrate that dHyperLbCas12a effectors can be used to dissect the independent and combinatorial contributions of CREs to gene expression. These tools create possibilities for highly multiplexed control of gene expression in many biological systems.
    DOI:  https://doi.org/10.1038/s41467-026-69090-z
  12. Mol Syst Biol. 2026 Feb 09.
    Dissecting reversible and irreversible single cell state transitions from gene regulatory networks.
    Daniel A Ramirez, Mingyang Lu.
      Understanding cell state transitions and their governing regulatory mechanisms remains one of the fundamental questions in biology. We develop a computational method, state transition inference using cross-cell correlations (STICCC), for predicting reversible and irreversible cell state transitions at single-cell resolution by using gene expression data and a set of gene regulatory interactions. The method is inspired by the fact that the gene expression time delays between regulators and targets can be exploited to infer past and future gene expression states. From applications to both simulated and experimental single-cell gene expression data, we show that STICCC-inferred vector fields capture basins of attraction and irreversible fluxes. By connecting regulatory information with systems' dynamical behaviors, STICCC reveals how network interactions influence reversible and irreversible state transitions. Compared to existing methods that infer pseudotime and RNA velocity, STICCC provides complementary insights into the gene regulation of cell state transitions.
    Keywords:  Cell State Transition; Gene Regulatory Network (GRN); RNA Velocity; Single Cell RNA-seq; Systems Biology
    DOI:  https://doi.org/10.1038/s44320-026-00196-8
  13. Nucleic Acids Res. 2026 Feb 05. pii: gkag050. [Epub ahead of print]54(4):
    Histone H3 tail charge patterns govern nucleosome condensate formation and dynamics.
    Erin F Hammonds, Anurag Singh, Krishna K Suresh, Sean Yang, Sarah S Meidl Zahorodny, Ritika Gupta, Davit A Potoyan, Priya R Banerjee, Emma A Morrison.
      Emerging models of nuclear organization suggest that chromatin forms functionally distinct microenvironments through phase separation. As chromatin architecture is organized at the level of the nucleosome and regulated by histone post-translational modifications, we investigated how these known regulatory mechanisms influence nucleosome phase behavior. By systematically altering charge distribution within the H3 tail, we found that the terminal and central regions modulate the phase boundary and tune nucleosome condensate viscosity differentially, as revealed by microscopy-based assays, microrheology, and simulations. Nuclear magnetic resonance relaxation experiments revealed that H3 tails remain dynamically mobile within condensates, and their mobility correlates with condensate viscosity. These results demonstrate that the number, identity, and spatial arrangement of basic residues in the H3 tail critically regulate nucleosome phase separation. Our findings support a model in which nucleosomes, through their intrinsic properties and modifications, actively shape the local chromatin microenvironment-providing new insight into the histone language in chromatin condensates.
    DOI:  https://doi.org/10.1093/nar/gkag050
  14. Science. 2026 Feb 12. 391(6786): eads1246
    Transcription factor Etv3 controls the tolerogenic function of dendritic cells.
    Nicholas M Adams, Daniel Martinez-Krams, Eduardo Esteva, Ai C Ra, Allegra Iliadi Alexiou, Hua Jin, Tae Jin Yun, Rayan Sleiman Tellaoui, Tenny Mudianto, Emily Vollmer, Ekaterina Novikova, Yanjun Tan, William Huntley, Oleg Krichevsky, Igor Dolgalev, Peter Izmirly, Jill P Buyon, Andre L Moreira, Amanda W Lund, Boris Reizis.
      Dendritic cells (DCs) facilitate the maintenance of immunological tolerance in the steady state. We report that transcription factor Etv3 is preferentially expressed in mature DCs, including tissue-derived migratory DCs (migDCs), and facilitates their homeostatic maturation and CCR7-dependent migration. Mice with global or DC-specific deletion of Etv3 manifested the expansion of CD25low regulatory T (Treg) cells, spontaneous activation of conventional T cells, and multiorgan T cell infiltration. Etv3 deficiency exacerbated TLR7-driven systemic lupus erythematosus (SLE)-like disease, supporting the reported genetic association of human ETV3 with SLE. Etv3-deficient migDCs up-regulated multiple costimulatory molecules, including OX40 ligand (OX40L/TNFSF4), whose blockade partially rescued the Treg cell abnormalities. These results identify Etv3 as an essential regulator of the tolerogenic function of DCs and implicate it in the regulation of human autoimmunity.
    DOI:  https://doi.org/10.1126/science.ads1246
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