bims-crepig Biomed News
on Chromatin regulation and epigenetics in cell fate and cancer
Issue of 2025–04–06
twenty-two papers selected by
Connor Rogerson, University of Cambridge
  1. SWI/SNF complex-mediated ZNF410 cooperative binding maintains chromatin accessibility and enhancer activity.
  2. Transcription factor networks disproportionately enrich for heritability of blood cell phenotypes.
  3. Genomic context-dependent histone H3K36 methylation by three Drosophila methyltransferases and implications for dedicated chromatin readers.
  4. Ultrastable and versatile multimeric ensembles of FoxP3 on microsatellites.
  5. Mouse promoters are characterised by low occupancy and high turnover of RNA polymerase II.
  6. Cooperation of a polymerizing SAM domain and an intrinsically disordered region enables full SAMD1 function on chromatin.
  7. Genotype inference from aggregated chromatin accessibility data reveals genetic regulatory mechanisms.
  8. OGT prevents DNA demethylation and suppresses the expression of transposable elements in heterochromatin by restraining TET activity genome-wide.
  9. Selective phase separation of transcription factors is driven by orthogonal molecular grammar.
  10. Epigenetic mechanisms controlling human leukemia stem cells and therapy resistance.
  11. Interpreting regulatory mechanisms of Hippo signaling through a deep learning sequence model.
  12. Genetically regulated eRNA expression predicts chromatin contact frequency and reveals genetic mechanisms at GWAS loci.
  13. Decoding m6Am by simultaneous transcription-start mapping and methylation quantification.
  14. An updated compendium and reevaluation of the evidence for nuclear transcription factor occupancy over the mitochondrial genome.
  15. Mesenchymal Meis2 controls whisker development independently from trigeminal sensory innervation.
  16. The Hunchback transcription factor determines interneuron molecular identity, morphology, and presynapse targeting in the Drosophila NB5-2 lineage.
  17. H3K36 methylation stamps transcription resistive to preserve development in plants.
  18. Optical control of gene expression using a DNA G-quadruplex targeting reversible photoswitch.
  19. HAND1 level controls the specification of multipotent cardiac and extraembryonic progenitors from human pluripotent stem cells.
  20. In vivo CRISPR screening reveals epigenetic regulators of hepatobiliary plasticity.
  21. Fungal chromatin remodeler Isw1 modulates translation via regulating tRNA transcription.
  22. The histone variant H2A.W restricts heterochromatic crossovers in Arabidopsis.
  1. Cell Rep. 2025 Mar 28. pii: S2211-1247(25)00247-5. [Epub ahead of print]44(4): 115476
    SWI/SNF complex-mediated ZNF410 cooperative binding maintains chromatin accessibility and enhancer activity.
    Siyuan Xu, Chuxuan Peng, Ren Ren, Haowen Lu, Han Zhao, Sijian Xia, Yijie Shen, Bin Xu, Haoyue Zhang, Xiaodong Cheng, Gerd A Blobel, Xianjiang Lan.
      The clustering of multiple transcription factor binding sites (TFBSs) for the same TF has proved to be a pervasive feature of cis-regulatory elements in the eukaryotic genome. However, the contribution of binding sites within the homotypic clusters of TFBSs (HCTs) to TF binding and target gene expression remains to be understood. Here, we characterize the CHD4 enhancers that harbor unique functional ZNF410 HCTs genome wide. We uncover that ZNF410 controls chromatin accessibility and activity of the CHD4 enhancer regions. We demonstrate that ZNF410 binds to the HCTs in a collaborative fashion, further conferring transcriptional activation. In particular, three ZNF410 motifs (sub-HCTs) located at 3' end of the distal enhancer act as "switch motifs" to control chromatin accessibility and enhancer activity. Mechanistically, the SWI/SNF complex is selectively required to mediate cooperative ZNF410 binding for CHD4 expression. Together, our findings expose a complex functional hierarchy of homotypic clustered motifs, which cooperate to fine-tune target gene expression.
    Keywords:  CP: Molecular biology; SWI/SNF complex; ZNF410; chromatin accessibility; enhancer activity; homotypic clustered motifs; motif cooperation; transcription factor
    DOI:  https://doi.org/10.1016/j.celrep.2025.115476
  2. Science. 2025 Apr 04. 388(6742): 52-59
    Transcription factor networks disproportionately enrich for heritability of blood cell phenotypes.
    Jorge Diego Martin-Rufino, Alexis Caulier, Seayoung Lee, Nicole Castano, Emily King, Samantha Joubran, Marcus Jones, Seth R Goldman, Uma P Arora, Lara Wahlster, Eric S Lander, Vijay G Sankaran.
      Most phenotype-associated genetic variants map to noncoding regulatory regions of the human genome, but their mechanisms remain elusive in most cases. We developed a highly efficient strategy, Perturb-multiome, to simultaneously profile chromatin accessibility and gene expression in single cells with CRISPR-mediated perturbation of master transcription factors (TFs). We examined the connection between TFs, accessible regions, and gene expression across the genome throughout hematopoietic differentiation. We discovered that variants within TF-sensitive accessible chromatin regions in erythroid differentiation, although representing <0.3% of the genome, show a ~100-fold enrichment for blood cell phenotype heritability, which is substantially higher than that for other accessible chromatin regions. Our approach facilitates large-scale mechanistic understanding of phenotype-associated genetic variants by connecting key cis-regulatory elements and their target genes within gene regulatory networks.
    DOI:  https://doi.org/10.1126/science.ads7951
  3. Nucleic Acids Res. 2025 Mar 20. pii: gkaf202. [Epub ahead of print]53(6):
    Genomic context-dependent histone H3K36 methylation by three Drosophila methyltransferases and implications for dedicated chromatin readers.
    Muhunden Jayakrishnan, Magdalena Havlová, Václav Veverka, Catherine Regnard, Peter B Becker.
      Methylation of histone H3 at lysine 36 (H3K36me3) marks active chromatin. The mark is interpreted by epigenetic readers that assist transcription and safeguard chromatin fiber integrity. In Drosophila, the chromodomain protein MSL3 binds H3K36me3 at X-chromosomal genes to implement dosage compensation. The PWWP-domain protein JASPer recruits the JIL1 kinase to active chromatin on all chromosomes. Because depletion of K36me3 had variable, locus-specific effects on the interactions of those readers, we systematically studied K36 methylation in a defined cellular model. Contrasting prevailing models, we found that K36me1, K36me2, and K36me3 each contribute to distinct chromatin states. Monitoring the changing K36 methylation landscape upon depletion of the three methyltransferases Set2, NSD, and Ash1 revealed local, context-specific methylation signatures. Each methyltransferase governs K36 methylation in dedicated genomic regions, with minor overlaps. Set2 catalyzes K36me3 predominantly at transcriptionally active euchromatin. NSD places K36me2/3 at defined loci within pericentric heterochromatin and on weakly transcribed euchromatic genes. Ash1 deposits K36me1 at putative enhancers. The mapping of MSL3 and JASPer suggested that they bind K36me2 in addition to K36me3, which was confirmed by direct affinity measurement. This dual specificity attracts the readers to a broader range of chromosomal locations and increases the robustness of their actions.
    DOI:  https://doi.org/10.1093/nar/gkaf202
  4. Mol Cell. 2025 Mar 26. pii: S1097-2765(25)00198-4. [Epub ahead of print]
    Ultrastable and versatile multimeric ensembles of FoxP3 on microsatellites.
    Fangwei Leng, Raquel Merino-Urteaga, Xi Wang, Wenxiang Zhang, Taekjip Ha, Sun Hur.
      Microsatellites are essential genomic components increasingly linked to transcriptional regulation. FoxP3, a transcription factor critical for regulatory T cell (Treg) development, recognizes TTTG repeat microsatellites by forming multimers along DNA. However, FoxP3 also binds a broader range of TnG repeats (n = 2-5), often at the edges of accessible chromatin regions. This raises questions about how FoxP3 adapts to sequence variability and the potential role of nucleosomes. Using cryoelectron microscopy and single-molecule analyses, we show that murine FoxP3 assembles into various distinct supramolecular structures, depending on DNA sequence. This structural plasticity enables FoxP3 to bridge 2-4 DNA duplexes, forming ultrastable structures that coordinate multiple genomic loci. Nucleosomes further facilitate FoxP3 assembly by inducing local DNA bending, creating a nucleus that recruits distal DNA elements through multiway bridging. Our findings thus reveal FoxP3's unusual ability to shapeshift to accommodate evolutionarily dynamic microsatellites and its potential to reinforce chromatin boundaries and three-dimensional genomic architecture.
    Keywords:  DNA bridging; Foxp3; chromatin loops; microsatellites; multi-way bridging; nucleosome; regulatory T cells; short tandem repeats; supramolecular assemblies; transcription factor
    DOI:  https://doi.org/10.1016/j.molcel.2025.03.005
  5. Mol Syst Biol. 2025 Mar 31.
    Mouse promoters are characterised by low occupancy and high turnover of RNA polymerase II.
    Kasit Chatsirisupachai, Christina J I Moene, Rozemarijn Kleinendorst, Elisa Kreibich, Nacho Molina, Arnaud Krebs.
      The general transcription machinery and its occupancy at promoters are highly conserved across metazoans. This contrasts with the kinetics of mRNA production that considerably differ between model species such as Drosophila and mouse. The molecular basis for these kinetic differences is currently unknown. Here, we used Single-Molecule Footprinting to measure RNA Polymerase II (Pol II) occupancy, the fraction of DNA molecules bound, at promoters in mouse and Drosophila cell lines. Single-molecule data reveals that Pol II occupancy is on average 3-5 times more frequent at transcriptionally active Drosophila promoters than active mouse promoters. Kinetic modelling of the occupancy states suggests that these differences in Pol II occupancy are determined by the ratio between the transcription initiation and Pol II turnover rates. We used chemical perturbation of transcription initiation to determine Pol II turnover rate in both species. Integration of these data into the model shows that infrequent Pol II occupancy in mouse is explained by the combination of high Pol II turnover and low transcription initiation rates.
    Keywords:  Eukaryotic Transcription; Kinetic Modelling; Pol II Pausing; RNA Pol II; Single-molecule Genomics
    DOI:  https://doi.org/10.1038/s44320-025-00094-5
  6. Nucleic Acids Res. 2025 Mar 20. pii: gkaf259. [Epub ahead of print]53(6):
    Cooperation of a polymerizing SAM domain and an intrinsically disordered region enables full SAMD1 function on chromatin.
    Merle Geller, Yinghua Cao, Clara Simon, Bastian Stielow, Jingfei Xu, Pengshuai Wei, Andrea Nist, Iris Rohner, Lea Marie Jeude, Theresa Huber, Thorsten Stiewe, Zhanxin Wang, Robert Liefke.
      Transcription factors orchestrate gene expression through a myriad of complex mechanisms, encompassing collaborations with other transcription factors and the formation of multimeric complexes. The chromatin-binding protein SAMD1 [sterile alpha motif (SAM) domain-containing protein 1] binds to unmethylated CpG-rich DNA utilizing its N-terminal winged-helix (WH) domain. Additionally, its C-terminal SAM domain, which mediates interactions with itself and with L3MBTL3, is crucial for chromatin binding. The precise role of the SAM domain in this process remains unclear. Using structural analyses, we elucidated the distinct homopolymerization modes within the SAM domains of L3MBTL3 and SAMD1, alongside their heterodimerization architecture. Interestingly, SAMD1 necessitates not only the WH and SAM domain but also a proline/alanine-rich intrinsically disordered region (IDR) for efficient chromatin binding. The IDR is essential for the ability of SAMD1 to form large polymers, with its functionality determined by integrity rather than the specific sequence. Mutagenesis studies underscore the critical role of arginines within the IDR for polymerization, chromatin binding, and the biological function of SAMD1. These findings propose a model in which structured and unstructured regions of SAMD1 cooperate in a coordinated fashion to facilitate chromatin binding. This work provides new insights into the diverse mechanisms transcription factors employ to interact with chromatin and regulate gene expression.
    DOI:  https://doi.org/10.1093/nar/gkaf259
  7. Genome Biol. 2025 Mar 30. 26(1): 81
    Genotype inference from aggregated chromatin accessibility data reveals genetic regulatory mechanisms.
    Brandon M Wenz, Yuan He, Nae-Chyun Chen, Joseph K Pickrell, Jeremiah H Li, Max F Dudek, Taibo Li, Rebecca Keener, Benjamin F Voight, Christopher D Brown, Alexis Battle.
       BACKGROUND: Understanding the genetic causes underlying variability in chromatin accessibility can shed light on the molecular mechanisms through which genetic variants may affect complex traits. Thousands of ATAC-seq samples have been collected that hold information about chromatin accessibility across diverse cell types and contexts, but most of these are not paired with genetic information and come from distinct projects and laboratories.
    RESULTS: We report here joint genotyping, chromatin accessibility peak calling, and discovery of quantitative trait loci which influence chromatin accessibility (caQTLs), demonstrating the capability of performing caQTL analysis on a large scale in a diverse sample set without pre-existing genotype information. Using 10,293 profiling samples representing 1454 unique donor individuals across 653 studies from public databases, we catalog 24,159 caQTLs in total. After joint discovery analysis, we cluster samples based on accessible chromatin profiles to identify context-specific caQTLs. We find that caQTLs are strongly enriched for annotations of gene regulatory elements across diverse cell types and tissues and are often linked with genetic variation associated with changes in expression (eQTLs), indicating that caQTLs can mediate genetic effects on gene expression. We demonstrate sharing of causal variants for chromatin accessibility across human traits, enabling a more complete picture of the genetic mechanisms underlying complex human phenotypes.
    CONCLUSIONS: Our work provides a proof of principle for caQTL calling from previously ungenotyped samples and represents one of the largest, most diverse caQTL resources currently available, informing mechanisms of genetic regulation of gene expression and contribution to disease.
    DOI:  https://doi.org/10.1186/s13059-025-03538-1
  8. Nat Struct Mol Biol. 2025 Mar 28.
    OGT prevents DNA demethylation and suppresses the expression of transposable elements in heterochromatin by restraining TET activity genome-wide.
    Hugo Sepulveda, Xiang Li, Leo J Arteaga-Vazquez, Isaac F López-Moyado, Melina Brunelli, Lot Hernández-Espinosa, Xiaojing Yue, J Carlos Angel, Caitlin Brown, Zhen Dong, Natasha Jansz, Fabio Puddu, Aurélie Modat, Jamie Scotcher, Páidí Creed, Patrick H Kennedy, Cindy Manriquez-Rodriguez, Samuel A Myers, Robert Crawford, Geoffrey J Faulkner, Anjana Rao.
      O-GlcNAc transferase (OGT) interacts robustly with all three mammalian TET methylcytosine dioxygenases. Here we show that deletion of the Ogt gene in mouse embryonic stem (mES) cells results in a widespread increase in the TET product 5-hydroxymethylcytosine in both euchromatic and heterochromatic compartments, with a concomitant reduction in the TET substrate 5-methylcytosine at the same genomic regions. mES cells treated with an OGT inhibitor also displayed increased 5-hydroxymethylcytosine, and attenuating the TET1-OGT interaction in mES cells resulted in a genome-wide decrease of 5-methylcytosine, indicating that OGT restrains TET activity and limits inappropriate DNA demethylation in a manner that requires the TET-OGT interaction and the catalytic activity of OGT. DNA hypomethylation in OGT-deficient cells was accompanied by derepression of transposable elements predominantly located in heterochromatin. We suggest that OGT protects the genome against TET-mediated DNA demethylation and loss of heterochromatin integrity, preventing the aberrant increase in transposable element expression noted in cancer, autoimmune-inflammatory diseases, cellular senescence and aging.
    DOI:  https://doi.org/10.1038/s41594-025-01505-9
  9. Nat Commun. 2025 Mar 31. 16(1): 3087
    Selective phase separation of transcription factors is driven by orthogonal molecular grammar.
    Mark D Driver, Patrick R Onck.
      Protein production is critically dependent on gene transcription rates, which are regulated by RNA polymerase and a large collection of different transcription factors (TFs). How these transcription factors selectively address different genes is only partially known. Recent discoveries show that the differential condensation of separate TF families through phase separation may contribute to selectivity. Here we address this by conducting phase separation studies on six TFs from three different TF families with residue-scale coarse-grained molecular dynamics simulations. Our exploration of ternary TF phase diagrams reveals four dominant sticker motifs and two orthogonal driving forces that dictate the resultant condensate morphology, pointing to sequence-dependent orthogonal molecular grammar as a generic molecular mechanism that drives selective transcriptional condensation in gene expression.
    DOI:  https://doi.org/10.1038/s41467-025-58445-7
  10. Nat Commun. 2025 Apr 03. 16(1): 3196
    Epigenetic mechanisms controlling human leukemia stem cells and therapy resistance.
    Sumiko Takao, Victor Morell, Masahiro Uni, Alicia Slavit, Sophia Rha, Shuyuan Cheng, Laura K Schmalbrock, Fiona C Brown, Sergi Beneyto-Calabuig, Richard P Koche, Lars Velten, Alex Kentsis.
      Cancer stem cells are essential for initiation and therapy resistance of many cancers, including acute myeloid leukemias (AML). Here, we apply functional genomic profiling to diverse human leukemias, including high-risk MLL- and NUP98-rearranged specimens, using label tracing in vivo. Human leukemia propagation is mediated by a rare quiescent label-retaining cell (LRC) population undetectable by current immunophenotypic markers. AML quiescence is reversible, preserving genetic clonal competition and epigenetic inheritance. LRC quiescence is defined by distinct promoter-centered chromatin and gene expression dynamics controlled by an AP-1/ETS transcription factor network, where JUN is necessary and sufficient for LRC quiescence and associated with persistence and chemotherapy resistance in diverse patients. This enables prospective isolation and manipulation of immunophenotypically-varied leukemia stem cells, establishing the functions of epigenetic plasticity in leukemia development and therapy resistance. These findings offer insights into leukemia stem cell quiescence and the design of therapeutic strategies for their clinical identification and control.
    DOI:  https://doi.org/10.1038/s41467-025-58370-9
  11. Cell Genom. 2025 Mar 27. pii: S2666-979X(25)00077-1. [Epub ahead of print] 100821
    Interpreting regulatory mechanisms of Hippo signaling through a deep learning sequence model.
    Khyati Dalal, Charles McAnany, Melanie Weilert, Mary Cathleen McKinney, Sabrina Krueger, Julia Zeitlinger.
      Signaling pathway components are well studied, but how they mediate cell-type-specific transcription responses is an unresolved problem. Using the Hippo pathway in mouse trophoblast stem cells as a model, we show that the DNA binding of signaling effectors is driven by cell-type-specific sequence rules that can be learned genome wide by deep learning models. Through model interpretation and experimental validation, we show that motifs for the cell-type-specific transcription factor TFAP2C enhance TEAD4/YAP1 binding in a nucleosome-range and distance-dependent manner, driving synergistic enhancer activation. We also discovered that Tead double motifs are widespread, highly active canonical response elements. Molecular dynamics simulations suggest that TEAD4 binds them cooperatively through surprisingly labile protein-protein interactions that depend on the DNA template. These results show that the response to signaling pathways is encoded in the cis-regulatory sequences and that interpreting the rules reveals insights into the mechanisms by which signaling effectors influence cell-type-specific enhancer activity.
    Keywords:  BPNet; CRISPR-Cas9; ChIP-nexus; Hippo signaling pathway; TEAD4; YAP1; enhancer redesign; interpretable deep learning; molecular dynamics; mouse trophoblast stem cells; transcription factors
    DOI:  https://doi.org/10.1016/j.xgen.2025.100821
  12. Nat Commun. 2025 Apr 03. 16(1): 3193
    Genetically regulated eRNA expression predicts chromatin contact frequency and reveals genetic mechanisms at GWAS loci.
    Michael J Betti, Phillip Lin, Melinda C Aldrich, Eric R Gamazon.
      The biological functions of extragenic enhancer RNAs and their impact on disease risk remain relatively underexplored. In this work, we develop in silico models of genetically regulated expression of enhancer RNAs across 49 cell and tissue types, characterizing their degree of genetic control. Leveraging the estimated genetically regulated expression for enhancer RNAs and canonical genes in a large-scale DNA biobank (N > 70,000) and high-resolution Hi-C contact data, we train a deep learning-based model of pairwise three-dimensional chromatin contact frequency for enhancer-enhancer and enhancer-gene pairs in cerebellum and whole blood. Notably, the use of genetically regulated expression of enhancer RNAs provides substantial tissue-specific predictive power, supporting a role for these transcripts in modulating spatial chromatin organization. We identify schizophrenia-associated enhancer RNAs independent of GWAS loci using enhancer RNA-based TWAS and determine the causal effects of these enhancer RNAs using Mendelian randomization. Using enhancer RNA-based TWAS, we generate a comprehensive resource of tissue-specific enhancer associations with complex traits in the UK Biobank. Finally, we show that a substantially greater proportion (63%) of GWAS associations colocalize with causal regulatory variation when enhancer RNAs are included.
    DOI:  https://doi.org/10.1038/s41467-025-58023-x
  13. Elife. 2025 Mar 31. pii: RP104139. [Epub ahead of print]13
    Decoding m6Am by simultaneous transcription-start mapping and methylation quantification.
    Jianheng Fox Liu, Ben R Hawley, Luke S Nicholson, Samie R Jaffrey.
      N6,2'-O-dimethyladenosine (m6Am) is a modified nucleotide located at the first transcribed position in mRNA and snRNA that is essential for diverse physiological processes. m6Am mapping methods assume each gene uses a single start nucleotide. However, gene transcription usually involves multiple start sites, generating numerous 5' isoforms. Thus, gene-level annotations cannot capture the diversity of m6Am modification in the transcriptome. Here, we describe CROWN-seq, which simultaneously identifies transcription-start nucleotides and quantifies m6Am stoichiometry for each 5' isoform that initiates with adenosine. Using CROWN-seq, we map the m6Am landscape in nine human cell lines. Our findings reveal that m6Am is nearly always a high stoichiometry modification, with only a small subset of cellular mRNAs showing lower m6Am stoichiometry. We find that m6Am is associated with increased transcript expression and provide evidence that m6Am may be linked to transcription initiation associated with specific promoter sequences and initiation mechanisms. These data suggest a potential new function for m6Am in influencing transcription.
    Keywords:  FTO; PCIF1; RNA modifications; biochemistry; chemical biology; human; m6Am; small nuclear RNA; transcription
    DOI:  https://doi.org/10.7554/eLife.104139
  14. PLoS One. 2025 ;20(3): e0318796
    An updated compendium and reevaluation of the evidence for nuclear transcription factor occupancy over the mitochondrial genome.
    Georgi K Marinov, Vivekanandan Ramalingam, William J Greenleaf, Anshul Kundaje.
      In most eukaryotes, mitochondrial organelles contain their own genome, usually circular, which is the remnant of the genome of the ancestral bacterial endosymbiont that gave rise to modern mitochondria. Mitochondrial genomes are dramatically reduced in their gene content due to the process of endosymbiotic gene transfer to the nucleus; as a result most mitochondrial proteins are encoded in the nucleus and imported into mitochondria. This includes the components of the dedicated mitochondrial transcription and replication systems and regulatory factors, which are entirely distinct from the information processing systems in the nucleus. However, since the 1990s several nuclear transcription factors have been reported to act in mitochondria, and previously we identified 8 human and 3 mouse transcription factors (TFs) with strong localized enrichment over the mitochondrial genome using ChIP-seq (Chromatin Immunoprecipitation) datasets from the second phase of the ENCODE (Encyclopedia of DNA Elements) Project Consortium. Here, we analyze the greatly expanded in the intervening decade ENCODE compendium of TF ChIP-seq datasets (a total of 6,153 ChIP experiments for 942 proteins, of which 763 are sequence-specific TFs) combined with interpretative deep learning models of TF occupancy to create a comprehensive compendium of nuclear TFs that show evidence of association with the mitochondrial genome. We find some evidence for chrM occupancy for 50 nuclear TFs and two other proteins, with bZIP TFs emerging as most likely to be playing a role in mitochondria. However, we also observe that in cases where the same TF has been assayed with multiple antibodies and ChIP protocols, evidence for its chrM occupancy is not always reproducible. In the light of these findings, we discuss the evidential criteria for establishing chrM occupancy and reevaluate the overall compendium of putative mitochondrial-acting nuclear TFs.
    DOI:  https://doi.org/10.1371/journal.pone.0318796
  15. Elife. 2025 Apr 04. pii: RP100854. [Epub ahead of print]13
    Mesenchymal Meis2 controls whisker development independently from trigeminal sensory innervation.
    Mehmet Mahsum Kaplan, Erika Hudacova, Miroslav Matejcek, Haneen Tuaima, Jan Křivánek, Ondrej Machon.
      Hair follicle development is initiated by reciprocal molecular interactions between the placode-forming epithelium and the underlying mesenchyme. Cell fate transformation in dermal fibroblasts generates a cell niche for placode induction by activation of signaling pathways WNT, EDA, and FGF in the epithelium. These successive paracrine epithelial signals initiate dermal condensation in the underlying mesenchyme. Although epithelial signaling from the placode to mesenchyme is better described, little is known about primary mesenchymal signals resulting in placode induction. Using genetic approach in mice, we show that Meis2 expression in cells derived from the neural crest is critical for whisker formation and also for branching of trigeminal nerves. While whisker formation is independent of the trigeminal sensory innervation, MEIS2 in mesenchymal dermal cells orchestrates the initial steps of epithelial placode formation and subsequent dermal condensation. MEIS2 regulates the expression of transcription factor Foxd1, which is typical of pre-dermal condensation. However, deletion of Foxd1 does not affect whisker development. Overall, our data suggest an early role of mesenchymal MEIS2 during whisker formation and provide evidence that whiskers can normally develop in the absence of sensory innervation or Foxd1 expression.
    Keywords:  Foxd1; Meis2; Sox2; cranial nerves; developmental biology; hair follicle placode; mouse; whisker follicle
    DOI:  https://doi.org/10.7554/eLife.100854
  16. PLoS Biol. 2025 Mar 31. 23(3): e3002881
    The Hunchback transcription factor determines interneuron molecular identity, morphology, and presynapse targeting in the Drosophila NB5-2 lineage.
    Heather Q Pollington, Chris Q Doe.
      Interneuron diversity within the central nervous system (CNS) is essential for proper circuit assembly. Functional interneurons must integrate multiple features, including combinatorial transcription factor (TF) expression, axon/dendrite morphology, and connectivity to properly specify interneuronal identity. Yet, how these different interneuron properties are coordinately regulated remains unclear. Here we used the Drosophila neural progenitor, NB5-2, known to generate late-born interneurons in a proprioceptive circuit, to determine if the early-born temporal transcription factor (TTF), Hunchback (Hb), specifies early-born interneuron identity, including molecular profile, axon/dendrite morphology, presynapse targeting, and behavior. We found that prolonged Hb expression in NB5-2 increases the number of neurons expressing early-born TFs (Nervy, Nkx6, and Dbx) at the expense of late-born TFs (Runt and Zfh2); thus, Hb is sufficient to promote interneuron molecular identity. Hb is also sufficient to transform late-born neuronal morphology to early-born neuronal morphology. Furthermore, prolonged Hb promotes the relocation of late-born neuronal presynapses to early-born neuronal presynapse neuropil locations, consistent with a change in interneuron connectivity. Finally, we found that prolonged Hb expression led to defects in proprioceptive behavior, consistent with a failure to properly specify late-born interneurons in the proprioceptive circuit. We conclude that the Hb TTF is sufficient to specify multiple aspects of early-born interneuron identity, as well as disrupt late-born proprioceptive neuron function.
    DOI:  https://doi.org/10.1371/journal.pbio.3002881
  17. Nat Plants. 2025 Mar 31.
    H3K36 methylation stamps transcription resistive to preserve development in plants.
    Yao Yao, Jincong Zhou, Jiacheng Wang, Xue Lei, Anjie Jiang, Qianwen Sun.
      Eukaryotic euchromatin is the less-compact chromatin and is modified by many histone modifications such as H3 lysine 36 methylation (H3K36me). Here we report a new chromatin state, 'transcription resistive', which is differentiated from activation and silencing. Transcription resistive is stamped by H3K36me with almost undetectable transcription activity but open-chromatin state, and occupies most documented plant essential genes. Mutating SDG8, previously known as the major H3K36 methyltransferase in Arabidopsis, surprisingly elevates 78.7% of H3K36me3-marked resistive loci, which accounts for 39.4% of the coding genome. Genetically, SDG8 prevents H3K36me activity of SDG4 at short and intronless genes to secure plant fertility, while it collaborates with other H3K36me methyltransferases on long and intron-rich genes. Together, our results reveal that SDG8 is the primary sensor that suppresses excessive H3K36me, and uncovered that 'transcription resistive' is a conserved H3K36me-stamped novel transcription state in plants, highlighting the regulatory diversities and biological significance of H3K36 methylation in eukaryotes.
    DOI:  https://doi.org/10.1038/s41477-025-01962-6
  18. Nat Chem. 2025 Apr 03.
    Optical control of gene expression using a DNA G-quadruplex targeting reversible photoswitch.
    Xiaoyun Zhang, Somdutta Dhir, Larry Melidis, Yuqi Chen, Zutao Yu, Angela Simeone, Jochen Spiegel, Santosh Adhikari, Shankar Balasubramanian.
      Transcriptional regulation is a dynamic process that coordinates diverse cellular activities, and the use of small molecules to perturb gene expression has propelled our understanding of the fundamental regulatory mechanisms. However, small molecules typically lack the spatiotemporal precision required in highly non-invasive, controlled settings. Here we present the development of a cell-permeable small-molecule DNA G-quadruplex (G4) binder, termed G4switch, that can be reversibly toggled on and off by visible light. We have biophysically characterized the light-mediated control of G4 binding in vitro, followed by cellular, genomic mapping of G4switch to G4 targets in chromatin to confirm G4-selective, light-dependent binding in a cellular context. By deploying G4switch in living cells, we show spatiotemporal control over the expression of a set of G4-containing genes and G4-associated cell proliferation. Our studies demonstrate a chemical tool and approach to interrogate the dynamics of key biological processes directly at the molecular level in cells.
    DOI:  https://doi.org/10.1038/s41557-025-01792-1
  19. EMBO J. 2025 Mar 31.
    HAND1 level controls the specification of multipotent cardiac and extraembryonic progenitors from human pluripotent stem cells.
    Adam T Lynch, Naomi Phillips, Megan Douglas, Marta Dorgnach, I-Hsuan Lin, Antony D Adamson, Zoulfia Darieva, Jessica Whittle, Neil A Hanley, Nicoletta Bobola, Matthew J Birket.
      Diverse sets of progenitors contribute to the development of the embryonic heart, but the mechanisms of their specification have remained elusive. Here, using a human pluripotent stem cell (hPSC) model, we deciphered cardiac and non-cardiac lineage trajectories in differentiation and identified transcription factors underpinning cell specification, identity and function. We discovered a concentration-dependent, fate determining function for the basic helix-loop-helix transcription factor HAND1 in mesodermal progenitors and uncovered its gene regulatory network. At low expression level, HAND1 directs differentiation towards multipotent juxta-cardiac field progenitors able to make cardiomyocytes and epicardial cells, whereas at high level it promotes the development of extraembryonic mesoderm. Importantly, HAND1-low progenitors can be propagated in their multipotent state. This detailed mechanistic insight into human development has the potential to accelerate the delivery of effective disease modelling, including for congenital heart disease, and cell therapy-based regenerative medicine.
    Keywords:  Epicardial; Gene Regulatory Networks; HAND1; Juxta-cardiac Field; Single Cell
    DOI:  https://doi.org/10.1038/s44318-025-00409-0
  20. Genes Dev. 2025 Apr 01.
    In vivo CRISPR screening reveals epigenetic regulators of hepatobiliary plasticity.
    Jonathan H Sussman, Hector W Cure, Salina Yuan, Kenji Ito, Irfan A Asangani, Benjamin A Garcia, Ben Z Stanger, Takeshi Katsuda.
      Following prolonged liver injury, a small fraction of hepatocytes undergoes reprogramming to become cholangiocytes or biliary epithelial cells (BECs). This physiological process involves chromatin and transcriptional remodeling, but the epigenetic mediators are largely unknown. Here, we exploited a lineage-traced model of liver injury to investigate the role of histone post-translational modification in biliary reprogramming. Using mass spectrometry, we defined the repertoire of histone marks that are globally altered in quantity during reprogramming. Next, applying an in vivo CRISPR screening approach, we identified seven histone-modifying enzymes that alter the efficiency of hepatobiliary reprogramming. Among these, the histone methyltransferase and demethylase Nsd1 and Kdm2a were found to have reciprocal effects on H3K36 methylation that regulated the early and late stages of reprogramming, respectively. Although loss of Nsd1 and Kdm2a affected reprogramming efficiency, cells ultimately acquired the same transcriptomic states. These findings reveal that multiple chromatin regulators exert dynamic and complementary activities to achieve robust cell fate switching, serving as a model for the cell identity changes that occur in various forms of physiological metaplasia or reprogramming.
    Keywords:  CRISPR screening; cellular plasticity; epigenetics; hepatocyte; histone modifier; metaplasia; reprogramming
    DOI:  https://doi.org/10.1101/gad.352420.124
  21. Nucleic Acids Res. 2025 Mar 20. pii: gkaf225. [Epub ahead of print]53(6):
    Fungal chromatin remodeler Isw1 modulates translation via regulating tRNA transcription.
    Jing Wang, Yueqi Zhang, Jingrui Wang, Liuqin Wang, Binshan Li, Shuang Liu, Xuepeng Sun, Zhonghua Ma.
      Chromatin dynamics are essential for regulating DNA processes in response to environmental stimuli. Although ISWI-family enzymes are known to remodel chromatin by sliding nucleosomes in budding yeast, their functional roles and outputs in eukaryotes remain largely unknown. In this study, we investigated chromatin accessibility in the phytopathogenic fungus Fusarium graminearum treated with and without putrescine, a compound that rapidly induces the biosynthesis of the mycotoxin deoxynivalenol (DON). Putrescine globally alters chromatin accessibility, with the ATP-dependent chromatin remodeler FgIsw1 emerging as a key regulator. Unexpectedly, deletion of FgIsw1 did not affect the transcription of DON biosynthesis genes (Tri) but significantly disrupted transfer RNA (tRNA) transcription, leading to a dramatic decline in translation of DON biosynthesis enzymes. Mechanistically, FgIsw1 maintains nucleosome phasing in tRNA chromatin regions, ensuring efficient tRNA transcription. As a result, ΔFgIsw1 was unable to produce DON and lost its virulence on the host plant. These results highlight a novel role of chromatin remodelers in regulating protein translation through the control of tRNA transcription.
    DOI:  https://doi.org/10.1093/nar/gkaf225
  22. Proc Natl Acad Sci U S A. 2025 Apr 08. 122(14): e2413698122
    The histone variant H2A.W restricts heterochromatic crossovers in Arabidopsis.
    Namil Son, Heejin Kim, Jaeil Kim, Jihye Park, Dohwan Byun, Sang-Jun Park, Hyein Kim, Yeong Mi Park, Pierre Bourguet, Frédéric Berger, Kyuha Choi.
      Meiotic crossovers rearrange allele combinations and create offspring diversity. Crossovers occur nonrandomly along chromosomes, predominantly in distal euchromatin and less in pericentromeric heterochromatin marked with histone H3 lysine 9 dimethylation (H3K9me2) and the H2A variant H2A.W in Arabidopsis thaliana. Loss of H3K9me2 increases heterochromatic crossovers, but how H2A.W affects crossover formation in pericentromeric regions is unknown. Here, we report that H2A.W is required to restrict heterochromatic crossovers in Arabidopsis. Using meiosis-specific microRNA-induced gene silencing (meiMIGS) and fluorescence-tagged recombination reporters, we show that meiotic knockdown of H2A.W.6, H2A.W.7, and H2A.W.12 (meiMIGS-H2A.W.6/7/12) increases pericentromeric crossovers. High-resolution genomic maps of crossovers show that meiMIGS-H2A.W.6/7/12 enhances heterochromatic crossovers, similar to meiMIGS plants silencing the H3K9me2 pathway. Consistently, genome-wide crossover maps show that the mutants h2a.w.6, h2a.w.7, h2a.w.6 h2a.w.7, and h2a.w.6 h2a.w.7 h2a.w.12, but not h2a.w.12, exhibit a similar increase in heterochromatic crossovers to meiMIGS-H2A.W.6/7/12, demonstrating that H2A.W.6 and H2A.W.7 limit heterochromatic crossovers. Profiling of genome-wide nucleosome density using micrococcal nuclease sequencing reveals that h2a.w mutants with increased heterochromatic crossovers have increased heterochromatin accessibility, with lower H3K9me2 levels during meiosis. Our findings shed light on the role of H2A.W variants as heterochromatin compaction factors that suppress meiotic crossovers within the pericentromeric regions.
    Keywords:  Arabidopsis thaliana; H2A.W; heterochromatin; meiotic crossover
    DOI:  https://doi.org/10.1073/pnas.2413698122
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