bims-crepig Biomed News
on Chromatin regulation and epigenetics in cell fate and cancer
Issue of 2026–01–18
nine papers selected by
Connor Rogerson, University of Cambridge
  1. Genetic variation shapes the chromatin accessibility landscape and transcriptional responses in mouse adipose tissue.
  2. Temporal constraints on enhancer usage shape the regulation of limb gene transcription.
  3. Tissue-specific restriction of transposon-derived regulatory elements safeguards cell-type identity.
  4. NF-κB restrains nutrient-dependent transcription programs through chromatin modulation in Drosophila.
  5. Sequential RNA polymerase II activation drives human hematopoiesis.
  6. Comprehensive profiling of chromatin occupancy dynamics through the cell cycle.
  7. Nonlinear transcriptional responses to gradual modulation of transcription factor dosage.
  8. STAN, a computational framework for inferring spatially informed transcription factor activity.
  9. Dominant-negative TP53 mutations potentiated by the HSF1-regulated proteostasis network.
  1. PLoS Genet. 2026 Jan 16. 22(1): e1011716
    Genetic variation shapes the chromatin accessibility landscape and transcriptional responses in mouse adipose tissue.
    Juho Mononen, Mari Taipale, Marjo Malinen, Anna-Liisa Levonen, Anna-Kaisa Ruotsalainen, Luke Norton, Sami Heikkinen.
      Most of the disease associated genetic variants identified in genome wide association studies have been mapped to the non-coding regions of the genome. One of the leading mechanisms by which these variants are thought to affect disease susceptibility is by altering transcription factor (TF) binding. Even though inbred mouse strains have been commonly used to investigate polygenic diseases, less is known on how their genetic differences translate to the level of gene regulation and chromatin landscape. Here, we investigated how genetic variation affects chromatin accessibility in the epididymal white adipose tissue (eWAT) of C57BL/6J and 129S1/SvImJ mice, which are commonly used to study diet-induced obesity, fed either chow or high-fat diet. We show that differences in chromatin accessibility are almost exclusively strain-specific and driven by genetic variation. In addition, we integrate ATAC-seq (chromatin accessibility) and H3K27ac ChIP-seq (active regulatory regions) data to show that tissue-specific TF binding sites are commonly found in the active regulatory regions hosting TF motif altering variants in eWAT. Using footprint analysis, we also show that TF occupancy is consistent with TF binding motif scores at the genetically altered loci. In addition, we validate these findings by extending the analysis to ATAC-seq and H3K27ac ChIP-seq data obtained from the liver. We employ RNA-seq to show that differentially expressed genes are co-located with differentially accessible regions hosting genetic variants. Overall, our findings highlight the connection between differential chromatin accessibility and genetic variation across metabolically central tissues of a mouse model for polygenic obesity.
    DOI:  https://doi.org/10.1371/journal.pgen.1011716
  2. Nat Commun. 2026 Jan 12. 17(1): 5
    Temporal constraints on enhancer usage shape the regulation of limb gene transcription.
    Raquel Rouco, Antonella Rauseo, Fabrice Darbellay, Guillaume Sapin, Olimpia Bompadre, Lucille Lopez-Delisle, Guillaume Andrey.
      Enhancer repertoires orchestrate gene expression during embryonic development, shaping organ structure and function. Individual enhancers can act in overlapping or distinct spatial domains, but their temporal specificity and coordinated action over time remain poorly understood. Here, we identify temporally restricted enhancer repertoires at multiple loci involved in mouse limb development. To capture their dynamic roles, we introduce the regulatory trajectory framework comprising initiation, maintenance, and decommissioning of gene expression. Using a transgenic recorder at the Shox2 locus, we demonstrate that early enhancers initiate transcription, while late enhancers maintain it. Additionally, we found that changes in 3D topology associate with enhancer activities and that loss of enhancer-promoter contacts occurs during decommissioning. Finally, we show that Shox2 regulatory decommissioning can be driven by Hoxd13, a known antagonist of Shox2 expression. Overall, our work uncovers how temporally restricted enhancers generate complex expression patterns and sheds light on the dynamics of enhancer-promoter interactions.
    DOI:  https://doi.org/10.1038/s41467-025-66055-6
  3. Cell Rep. 2026 Jan 13. pii: S2211-1247(25)01589-X. [Epub ahead of print]45(1): 116817
    Tissue-specific restriction of transposon-derived regulatory elements safeguards cell-type identity.
    Danica Milovanović, Julien Duc, Wayo Matsushima, Romain Hamelin, Evarist Planet, Sandra Offner, Olga Rosspopoff, Didier Trono.
      Transposable elements (TEs) reshape mammalian cis-regulatory landscapes, but the mechanisms controlling their context-specific activity remain unclear. KRAB zinc finger proteins (KZFPs) typically repress TE-derived regulatory activity via TRIM28-mediated H3K9me3 deposition. We expand this paradigm by uncovering non-canonical KZFP-TE relationships. Through comprehensive epigenomic mapping of KZFP-bound TEs, we show that ancient mammalian L2/MIR elements' regulatory activity is delineated by KZFP binding despite low H3K9me3 enrichment. We dissect this relationship by focusing on ZNF436, a non-canonical KZFP highly expressed in the developing human heart. We find that ZNF436 preserves cardiomyocyte function by promoting cardiac gene expression while restricting alternative lineage programs. Mechanistically, ZNF436 associates with the SWI/SNF remodeling complex to limit the accessibility of L2/MIR-derived CREs, otherwise active in non-cardiac tissues. Our findings reveal a TRIM28-independent role for KZFPs in shaping cell-type-specific regulatory landscapes and emphasize the importance of repressing alternative lineage programs while activating lineage-specific ones to safeguard cell identity.
    Keywords:  CP: Developmental biology; CP: Molecular biology; KRAB zinc finger proteins; LINE/L2; SINE/MIR; SWI/SNF; cardiomyocyte differentiation; chromatin remodeling; cis-regulatory elements; enhancers; transposable elements
    DOI:  https://doi.org/10.1016/j.celrep.2025.116817
  4. Nucleic Acids Res. 2026 Jan 14. pii: gkaf1530. [Epub ahead of print]54(2):
    NF-κB restrains nutrient-dependent transcription programs through chromatin modulation in Drosophila.
    Xiangshuo Kong, Conghui Li, Jason Karpac.
      The co-evolution of immune and metabolic systems has endowed immune signaling pathways with distinct control of cellular metabolism. Innate immune transcription factors, such as nuclear factor κB (NF-κB), have thus emerged as key regulators of adaptive metabolic responses to changes in diet and nutrition. Utilizing chromatin accessibility genomics, we found that Drosophila NF-κB (Relish) can restrain nutrient-dependent metabolic transcriptional programs that control cellular catabolism of energy substrates, divergent from the protein's canonical role as a transcriptional activator. NF-κB/Relish restricts chromatin accessibility through modulating histone acetylation at metabolic target gene loci, which restrains metabolic gene transcription and blocks excessive activation of nutrient-dependent metabolic programs. Targeted genetic screening revealed that histone deacetylase 6 interacts with NF-κB/Relish at NF-κB DNA regulatory motifs to limit chromatin accessibility and repress metabolic transcriptional programs. These results highlight that innate immune transcription factors can epigenetically restrain cellular catabolism to fine-tune nutrient-dependent metabolic adaptation.
    DOI:  https://doi.org/10.1093/nar/gkaf1530
  5. Cell Rep. 2026 Jan 09. pii: S2211-1247(25)01574-8. [Epub ahead of print]45(1): 116802
    Sequential RNA polymerase II activation drives human hematopoiesis.
    Derek H Janssens, Christine A Codomo, Dominik J Otto, Lev Silberstein, Kami Ahmad, Steve Henikoff.
      Promoter-proximal pausing of RNA polymerase II (Pol II) primes genes for rapid activation, yet how Pol II dynamics are temporally organized in adult stem cells to enable fast and flexible responses to environmental cues remain unknown. To address this, we developed sciCUT&Tag2in1 for joint profiling of Pol II and histone modifications in single cells. By profiling over 200,000 CD34+ hematopoietic stem cells (HSCs) and progenitors, we identify a Pol II regulatory cascade that directs the response to granulocyte colony-stimulating factor (G-CSF)-induced inflammatory stress. HSCs are activated by elevated Pol II occupancy and reduced Polycomb repression of immune response genes. Lineage commitment proceeds through sequential modes of Pol II activation, beginning with rapid pause-and-release genes, followed by slower initiate-and-release of Polycomb-repressed targets. sciCUT&Tag2in1 defines the temporal logic of how adult stem cells use paused Pol II to enable flexible lineage decisions, providing a powerful tool for studying the intersection of development, inflammation, and disease.
    Keywords:  CP: molecular biology; CP: stem cell research; CUT&Tag; G-CSF response; RNA polymerase II; hematopoietic stem cells; inflammatory memory; lineage commitment; polycomb repression; sciCUT&Tag2in1; single-cell genomics; transcriptional pausing
    DOI:  https://doi.org/10.1016/j.celrep.2025.116802
  6. Nucleic Acids Res. 2026 Jan 14. pii: gkaf1385. [Epub ahead of print]54(2):
    Comprehensive profiling of chromatin occupancy dynamics through the cell cycle.
    Yulong Li, David M MacAlpine, Alexander J Hartemink.
      The occupancy of DNA-binding factors is critical for establishing the chromatin context of DNA-templated processes like transcription and replication. Many studies have investigated relationships between chromatin and transcription in response to genetic and environmental perturbations, but a comprehensive view of the dynamics of chromatin organization and its effect on transcription during the cell-intrinsic process of the cell division cycle has been lacking. In this study, we use the model organism Saccharomyces cerevisiae to investigate the interplay between the cell-cycle-regulated dynamics of chromatin and transcription. In a time series across two consecutive cell cycles, we profile the genome-wide chromatin occupancy landscape with next-generation sequencing of micrococcal-nuclease-digested chromatin while simultaneously profiling the transcriptome with RNA-seq. Surprisingly, among cell-cycle-regulated genes, only a small subset exhibits a change in protein occupancy in their promoter or gene body that strongly mirrors the dynamics of their expression level. However, we separately identify widespread chromatin changes that are not directly linked to cell-cycle-regulated genes, revealing transcription-independent chromatin dynamics during cell-cycle progression. Using entropy as a proxy for nucleosome disorganization, we observe widespread nucleosome disruption in S phase followed by re-organization in M phase, associated with replicative and mitotic activities, respectively. A notable exception is the set of genes expressed in mitosis, which exhibit marked M-phase nucleosome disorganization, likely due to elevated transcription. We develop a Gaussian process statistical model that uses simple features from these chromatin data to improve the prediction of transcript dynamics through the cell cycle. Collectively, our data reveal complex relationships between the dynamics of chromatin occupancy, transcription, and replication during the cell cycle.
    DOI:  https://doi.org/10.1093/nar/gkaf1385
  7. Elife. 2026 Jan 14. pii: RP100555. [Epub ahead of print]13
    Nonlinear transcriptional responses to gradual modulation of transcription factor dosage.
    Júlia Domingo, Mariia Minaeva, John A Morris, Samuel Ghatan, Marcello Ziosi, Neville E Sanjana, Tuuli Lappalainen.
      Genomic loci associated with common traits and diseases are typically non-coding and likely impact gene expression, sometimes coinciding with rare loss-of-function variants in the target gene. However, our understanding of how gradual changes in gene dosage affect molecular, cellular, and organismal traits is currently limited. To address this gap, we induced gradual changes in gene expression of four genes using CRISPR activation and inactivation in human-derived K562 cells. Downstream transcriptional consequences of dosage modulation of three master trans-regulators associated with blood cell traits (GFI1B, NFE2, and MYB) were examined using targeted single-cell multimodal sequencing. We showed that guide tiling around the TSS is the most effective way to modulate cis gene expression across a wide range of fold changes, with further effects from chromatin accessibility and histone marks that differ between the inhibition and activation systems. Our single-cell data allowed us to precisely detect subtle to large gene expression changes in dozens of trans genes, revealing that many responses to dosage changes of these three TFs are nonlinear, including non-monotonic behaviours, even when constraining the fold changes of the master regulators to a copy number gain or loss. We found that the dosage properties are linked to gene constraint and that some of these nonlinear responses are enriched for disease and GWAS genes. Overall, our study provides a straightforward and scalable method to precisely modulate gene expression and gain insights into its downstream consequences at high resolution.
    Keywords:  computational biology; gene expression; gene regulation; human; systems biology; transcription factors
    DOI:  https://doi.org/10.7554/eLife.100555
  8. Nucleic Acids Res. 2026 Jan 05. pii: gkaf1473. [Epub ahead of print]54(1):
    STAN, a computational framework for inferring spatially informed transcription factor activity.
    Linan Zhang, April Sagan, Bin Qin, Haoyu Wang, Elena Kim, Baoli Hu, Hatice Ulku Osmanbeyoglu.
      Transcription factors (TFs) orchestrate cellular responses to environmental signals and intercellular communication. The activity of TFs is influenced by neighboring cells, impacting cellular fate and function. Spatial transcriptomics (ST) allows for the mapping of mRNA expression across tissue samples, providing insights into the local microenvironment. However, the potential of ST data to systematically infer TF activity and its role in cell identity has not been fully exploited. We introduce STAN (Spatially informed Transcription factor Activity Network), a linear mixed-effects computational approach that predicts spatially informed, spot-specific TF activities by integrating curated TF-target gene priors, mRNA expression, spatial coordinates, and histological features. We demonstrate the utility of STAN on lymph node, dorsolateral prefrontal cortex, breast cancer, and glioblastoma ST datasets, identifying TFs associated with specific cell types, spatial regions, pathological zones, and ligand-receptor pairs. STAN enhances the utility of ST data, revealing the intricate interplay between TFs and spatial organization in diverse biological contexts.
    DOI:  https://doi.org/10.1093/nar/gkaf1473
  9. Mol Cell. 2026 Jan 14. pii: S1097-2765(25)00987-6. [Epub ahead of print]
    Dominant-negative TP53 mutations potentiated by the HSF1-regulated proteostasis network.
    Stephanie Halim, Rebecca M Sebastian, Kristi E Liivak, Jessica E Patrick, Tiffani Hui, David R Amici, Andrew O Giacomelli, Paulina Rios, Vincent L Butty, William C Hahn, Francisco J Sánchez-Rivera, Marc L Mendillo, Yu-Shan Lin, Matthew D Shoulders.
      Protein mutational landscapes are shaped by how amino acid substitutions affect stability and folding or aggregation kinetics. These properties are modulated by cellular proteostasis networks. Heat shock factor 1 (HSF1) is the master regulator of cytosolic and nuclear proteostasis. Chronic HSF1 activity upregulation is a hallmark of cancer cells, potentially because upregulated proteostasis factors facilitate the acquisition and maintenance of oncogenic mutations. Here, we assess how HSF1 activation influences mutational trajectories by which p53 can escape cytotoxic pressure from nutlin-3, an inhibitor of the p53 regulator mouse double minute 2 homolog (MDM2). HSF1 activation broadly increases the fitness of dominant-negative p53 substitutions, particularly non-conservative, biophysically unfavorable amino acid changes within buried regions of the p53 DNA-binding domain. These findings demonstrate that HSF1 activation reshapes the oncogenic mutational landscape by preferentially supporting the emergence and persistence of biophysically disruptive, cancer-associated p53 substitutions, linking proteostasis network activity directly to oncogenic evolution.
    Keywords:  HSP70; HSP90; cancer evolution; chaperones; deep mutational scanning; heat shock factor I; mutational buffering; p53; protein folding; proteostasis
    DOI:  https://doi.org/10.1016/j.molcel.2025.12.013
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