bims-crepig Biomed News
on Chromatin regulation and epigenetics in cell fate and cancer
Issue of 2024‒05‒26
sixteen papers selected by
Connor Rogerson, University of Cambridge
  1. TET activity safeguards pluripotency throughout embryonic dormancy.
  2. A chromatin code for limb segment identity in axolotl limb regeneration.
  3. Active transcription and epigenetic reactions synergistically regulate meso-scale genomic organization.
  4. YAP condensates are highly organized hubs.
  5. Dynamic RNA polymerase II occupancy drives differentiation of the intestine under the direction of HNF4.
  6. Using a comprehensive atlas and predictive models to reveal the complexity and evolution of brain-active regulatory elements.
  7. Contribution of CENP-F to FOXM1-Mediated Discordant Centromere and Kinetochore Transcriptional Regulation.
  8. Sequence reliance of the Drosophila context-dependent transcription factor CLAMP.
  9. Transcription decouples estrogen-dependent changes in enhancer-promoter contact frequencies and spatial proximity.
  10. Angle between DNA linker and nucleosome core particle regulates array compaction revealed by individual-particle cryo-electron tomography.
  11. Comparative cofactor screens show the influence of transactivation domains and core promoters on the mechanisms of transcription.
  12. Histone H1.0 couples cellular mechanical behaviors to chromatin structure.
  13. Machine learning identifies activation of RUNX/AP-1 as drivers of mesenchymal and fibrotic regulatory programs in gastric cancer.
  14. DNA methylation-based high-resolution mapping of long-distance chromosomal interactions in nucleosome-depleted regions.
  15. The SUN-family protein Sad1 mediates heterochromatin spatial organization through interaction with histone H2A-H2B.
  16. Cell of origin epigenetic priming determines susceptibility to Tet2 mutation.
  1. Nat Struct Mol Biol. 2024 May 23.
    TET activity safeguards pluripotency throughout embryonic dormancy.
    Maximilian Stötzel, Chieh-Yu Cheng, Ibrahim A IIik, Abhishek Sampath Kumar, Persia Akbari Omgba, Vera A van der Weijden, Yufei Zhang, Martin Vingron, Alexander Meissner, Tuğçe Aktaş, Helene Kretzmer, Aydan Bulut-Karslioğlu.
      Dormancy is an essential biological process for the propagation of many life forms through generations and stressful conditions. Early embryos of many mammals are preservable for weeks to months within the uterus in a dormant state called diapause, which can be induced in vitro through mTOR inhibition. Cellular strategies that safeguard original cell identity within the silent genomic landscape of dormancy are not known. Here we show that the protection of cis-regulatory elements from silencing is key to maintaining pluripotency in the dormant state. We reveal a TET-transcription factor axis, in which TET-mediated DNA demethylation and recruitment of methylation-sensitive transcription factor TFE3 drive transcriptionally inert chromatin adaptations during dormancy transition. Perturbation of TET activity compromises pluripotency and survival of mouse embryos under dormancy, whereas its enhancement improves survival rates. Our results reveal an essential mechanism for propagating the cellular identity of dormant cells, with implications for regeneration and disease.
    DOI:  https://doi.org/10.1038/s41594-024-01313-7
  2. Dev Cell. 2024 May 21. pii: S1534-5807(24)00300-9. [Epub ahead of print]
    A chromatin code for limb segment identity in axolotl limb regeneration.
    Akane Kawaguchi, Jingkui Wang, Dunja Knapp, Prayag Murawala, Sergej Nowoshilow, Wouter Masselink, Yuka Taniguchi-Sugiura, Ji-Feng Fei, Elly M Tanaka.
      The salamander limb correctly regenerates missing limb segments because connective tissue cells have segment-specific identities, termed "positional information". How positional information is molecularly encoded at the chromatin level has been unknown. Here, we performed genome-wide chromatin profiling in mature and regenerating axolotl limb connective tissue cells. We find segment-specific levels of histone H3K27me3 as the major positional mark, especially at limb homeoprotein gene loci but not their upstream regulators, constituting an intrinsic segment information code. During regeneration, regeneration-specific regulatory elements became active prior to the re-appearance of developmental regulatory elements. In the hand, the permissive chromatin state of the homeoprotein gene HoxA13 engages with the regeneration program bypassing the upper limb program. Comparison of regeneration regulatory elements with those found in other regenerative animals identified a core shared set of transcription factors, supporting an ancient, conserved regeneration program.
    Keywords:  conserved regeneration program; genome-wide chromatin profiling; homeoprotein gene; limb regeneration; positional information; regeneration-specific regulatory elements
    DOI:  https://doi.org/10.1016/j.devcel.2024.05.002
  3. Nat Commun. 2024 May 21. 15(1): 4338
    Active transcription and epigenetic reactions synergistically regulate meso-scale genomic organization.
    Aayush Kant, Zixian Guo, Vinayak Vinayak, Maria Victoria Neguembor, Wing Shun Li, Vasundhara Agrawal, Emily Pujadas, Luay Almassalha, Vadim Backman, Melike Lakadamyali, Maria Pia Cosma, Vivek B Shenoy.
      In interphase nuclei, chromatin forms dense domains of characteristic sizes, but the influence of transcription and histone modifications on domain size is not understood. We present a theoretical model exploring this relationship, considering chromatin-chromatin interactions, histone modifications, and chromatin extrusion. We predict that the size of heterochromatic domains is governed by a balance among the diffusive flux of methylated histones sustaining them and the acetylation reactions in the domains and the process of loop extrusion via supercoiling by RNAPII at their periphery, which contributes to size reduction. Super-resolution and nano-imaging of five distinct cell lines confirm the predictions indicating that the absence of transcription leads to larger heterochromatin domains. Furthermore, the model accurately reproduces the findings regarding how transcription-mediated supercoiling loss can mitigate the impacts of excessive cohesin loading. Our findings shed light on the role of transcription in genome organization, offering insights into chromatin dynamics and potential therapeutic targets.
    DOI:  https://doi.org/10.1038/s41467-024-48698-z
  4. iScience. 2024 Jun 21. 27(6): 109927
    YAP condensates are highly organized hubs.
    Siyuan Hao, Ye Jin Lee, Nadav Benhamou Goldfajn, Eduardo Flores, Jindayi Liang, Hannah Fuehrer, Justin Demmerle, Jennifer Lippincott-Schwartz, Zhe Liu, Shahar Sukenik, Danfeng Cai.
      YAP/TEAD signaling is essential for organismal development, cell proliferation, and cancer progression. As a transcriptional coactivator, how YAP activates its downstream target genes is incompletely understood. YAP forms biomolecular condensates in response to hyperosmotic stress, concentrating transcription-related factors to activate downstream target genes. However, whether YAP forms condensates under other signals, how YAP condensates organize and function, and how YAP condensates activate transcription in general are unknown. Here, we report that endogenous YAP forms sub-micron scale condensates in response to Hippo pathway regulation and actin cytoskeletal tension. YAP condensates are stabilized by the transcription factor TEAD1, and recruit BRD4, a coactivator that is enriched at active enhancers. Using single-particle tracking, we found that YAP condensates slowed YAP diffusion within condensate boundaries, a possible mechanism for promoting YAP target search. These results reveal that YAP condensate formation is a highly regulated process that is critical for YAP/TEAD target gene expression.
    Keywords:  Biophysics; molecular interaction; molecular mechanism of gene regulation; properties of biomolecules; protein
    DOI:  https://doi.org/10.1016/j.isci.2024.109927
  5. Cell Rep. 2024 May 19. pii: S2211-1247(24)00570-9. [Epub ahead of print]43(6): 114242
    Dynamic RNA polymerase II occupancy drives differentiation of the intestine under the direction of HNF4.
    Kiranmayi Vemuri, Sneha Kumar, Lei Chen, Michael P Verzi.
      Terminal differentiation requires massive restructuring of the transcriptome. During intestinal differentiation, the expression patterns of nearly 4,000 genes are altered as cells transition from progenitor cells in crypts to differentiated cells in villi. We identify dynamic occupancy of RNA polymerase II (Pol II) to gene promoters as the primary driver of transcriptomic shifts during intestinal differentiation in vivo. Changes in enhancer-promoter looping interactions accompany dynamic Pol II occupancy and are dependent upon HNF4, a pro-differentiation transcription factor. Using genetic loss-of-function, chromatin immunoprecipitation sequencing (ChIP-seq), and immunoprecipitation (IP) mass spectrometry, we demonstrate that HNF4 collaborates with chromatin remodelers and loop-stabilizing proteins and facilitates Pol II occupancy at hundreds of genes pivotal to differentiation. We also explore alternate mechanisms that drive differentiation gene expression and find that pause-release of Pol II and post-transcriptional mRNA stability regulate smaller subsets of differentially expressed genes. These studies provide insights into the mechanisms of differentiation in renewing adult tissue.
    Keywords:  CP: Genomics; CP: Molecular biology; HNF4 transcription factors; Pol II ChIP-seq; RNA polymerase II; chromatin looping; crypt-villus axis; dynamic Pol II occupancy; intestinal epithelium; post-transcriptional gene regulation; promoter-proximal pausing; rapid immunoprecipitation mass spectrometry of endogenous proteins
    DOI:  https://doi.org/10.1016/j.celrep.2024.114242
  6. Sci Adv. 2024 May 24. 10(21): eadj4452
    Using a comprehensive atlas and predictive models to reveal the complexity and evolution of brain-active regulatory elements.
    Henry E Pratt, Gregory Andrews, Nicole Shedd, Nishigandha Phalke, Tongxin Li, Anusri Pampari, Matthew Jensen, Cindy Wen, PsychENCODE Consortium, Michael J Gandal, Daniel H Geschwind, Mark Gerstein, Jill Moore, Anshul Kundaje, Andrés Colubri, Zhiping Weng.
      Most genetic variants associated with psychiatric disorders are located in noncoding regions of the genome. To investigate their functional implications, we integrate epigenetic data from the PsychENCODE Consortium and other published sources to construct a comprehensive atlas of candidate brain cis-regulatory elements. Using deep learning, we model these elements' sequence syntax and predict how binding sites for lineage-specific transcription factors contribute to cell type-specific gene regulation in various types of glia and neurons. The elements' evolutionary history suggests that new regulatory information in the brain emerges primarily via smaller sequence mutations within conserved mammalian elements rather than entirely new human- or primate-specific sequences. However, primate-specific candidate elements, particularly those active during fetal brain development and in excitatory neurons and astrocytes, are implicated in the heritability of brain-related human traits. Additionally, we introduce PsychSCREEN, a web-based platform offering interactive visualization of PsychENCODE-generated genetic and epigenetic data from diverse brain cell types in individuals with psychiatric disorders and healthy controls.
    DOI:  https://doi.org/10.1126/sciadv.adj4452
  7. Mol Cell Biol. 2024 May 23. 1-17
    Contribution of CENP-F to FOXM1-Mediated Discordant Centromere and Kinetochore Transcriptional Regulation.
    Sakshi Khurana, Dileep Varma, Daniel R Foltz.
      Proper chromosome segregation is required to ensure chromosomal stability. The centromere (CEN) is a unique chromatin domain defined by CENP-A and is responsible for recruiting the kinetochore (KT) during mitosis, ultimately regulating microtubule spindle attachment and mitotic checkpoint function. Upregulation of many CEN/KT genes is commonly observed in cancer. Here, we show that although FOXM1 occupies promoters of many CEN/KT genes with MYBL2, FOXM1 overexpression alone is insufficient to drive the FOXM1-correlated transcriptional program. CENP-F is canonically an outer kinetochore component; however, it functions with FOXM1 to coregulate G2/M transcription and proper chromosome segregation. Loss of CENP-F results in altered chromatin accessibility at G2/M genes and reduced FOXM1-MBB complex formation. We show that coordinated CENP-FFOXM1 transcriptional regulation is a cancer-specific function. We observe a small subset of CEN/KT genes including CENP-C, that are not regulated by FOXM1. Upregulation of CENP-C in the context of CENP-A overexpression leads to increased chromosome missegregation and cell death suggesting that escape of CENP-C from FOXM1 regulation is a cancer survival mechanism. Together, we show that FOXM1 and CENP-F coordinately regulate G2/M genes, and this coordination is specific to a subset of genes to allow for maintenance of chromosome instability levels and subsequent cell survival.
    Keywords:  Centromere; cell cycle; chromosome segregation; kinetochore; transcriptional regulation
    DOI:  https://doi.org/10.1080/10985549.2024.2350543
  8. Genetics. 2024 May 22. pii: iyae060. [Epub ahead of print]
    Sequence reliance of the Drosophila context-dependent transcription factor CLAMP.
    Lauren J Hodkinson, Julia Gross, Casey A Schmidt, Pamela P Diaz-Saldana, Tsutomo Aoki, Leila E Rieder.
      Despite binding similar cis elements in multiple locations, a single transcription factor (TF) often performs context-dependent functions at different loci. How factors integrate cis sequence and genomic context is still poorly understood and has implications for off-target effects in genetic engineering. The Drosophila context-dependent TF chromatin-linked adaptor for male-specific lethal proteins (CLAMP) targets similar GA-rich cis elements on the X-chromosome and at the histone gene locus but recruits very different, locus-specific factors. We discover that CLAMP leverages information from both cis element and local sequence to perform context-specific functions. Our observations imply the importance of other cues, including protein-protein interactions and the presence of additional cofactors.
    Keywords:   Drosophila ; CLAMP; HLB; MSL complex; Mxc; context specificity; histone genes; transcription factor
    DOI:  https://doi.org/10.1093/genetics/iyae060
  9. PLoS Genet. 2024 May 23. 20(5): e1011277
    Transcription decouples estrogen-dependent changes in enhancer-promoter contact frequencies and spatial proximity.
    Luciana I Gómez Acuña, Ilya Flyamer, Shelagh Boyle, Elias T Friman, Wendy A Bickmore.
      How enhancers regulate their target genes in the context of 3D chromatin organization is extensively studied and models which do not require direct enhancer-promoter contact have recently emerged. Here, we use the activation of estrogen receptor-dependent enhancers in a breast cancer cell line to study enhancer-promoter communication at two loci. This allows high temporal resolution tracking of molecular events from hormone stimulation to efficient gene activation. We examine how both enhancer-promoter spatial proximity assayed by DNA fluorescence in situ hybridization, and contact frequencies resulting from chromatin in situ fragmentation and proximity ligation, change dynamically during enhancer-driven gene activation. These orthogonal methods produce seemingly paradoxical results: upon enhancer activation enhancer-promoter contact frequencies increase while spatial proximity decreases. We explore this apparent discrepancy using different estrogen receptor ligands and transcription inhibitors. Our data demonstrate that enhancer-promoter contact frequencies are transcription independent whereas altered enhancer-promoter proximity depends on transcription. Our results emphasize that the relationship between contact frequencies and physical distance in the nucleus, especially over short genomic distances, is not always a simple one.
    DOI:  https://doi.org/10.1371/journal.pgen.1011277
  10. Nat Commun. 2024 May 23. 15(1): 4395
    Angle between DNA linker and nucleosome core particle regulates array compaction revealed by individual-particle cryo-electron tomography.
    Meng Zhang, César Díaz-Celis, Jianfang Liu, Jinhui Tao, Paul D Ashby, Carlos Bustamante, Gang Ren.
      The conformational dynamics of nucleosome arrays generate a diverse spectrum of microscopic states, posing challenges to their structural determination. Leveraging cryogenic electron tomography (cryo-ET), we determine the three-dimensional (3D) structures of individual mononucleosomes and arrays comprising di-, tri-, and tetranucleosomes. By slowing the rate of condensation through a reduction in ionic strength, we probe the intra-array structural transitions that precede inter-array interactions and liquid droplet formation. Under these conditions, the arrays exhibite irregular zig-zag conformations with loose packing. Increasing the ionic strength promoted intra-array compaction, yet we do not observe the previously reported regular 30-nanometer fibers. Interestingly, the presence of H1 do not induce array compaction; instead, one-third of the arrays display nucleosomes invaded by foreign DNA, suggesting an alternative role for H1 in chromatin network construction. We also find that the crucial parameter determining the structure adopted by chromatin arrays is the angle between the entry and exit of the DNA and the corresponding tangents to the nucleosomal disc. Our results provide insights into the initial stages of intra-array compaction, a critical precursor to condensation in the regulation of chromatin organization.
    DOI:  https://doi.org/10.1038/s41467-024-48305-1
  11. Nat Genet. 2024 May 20.
    Comparative cofactor screens show the influence of transactivation domains and core promoters on the mechanisms of transcription.
    Charles C Bell, Jesse J Balic, Laure Talarmain, Andrea Gillespie, Laura Scolamiero, Enid Y N Lam, Ching-Seng Ang, Geoffrey J Faulkner, Omer Gilan, Mark A Dawson.
      Eukaryotic transcription factors (TFs) activate gene expression by recruiting cofactors to promoters. However, the relationships between TFs, promoters and their associated cofactors remain poorly understood. Here we combine GAL4-transactivation assays with comparative CRISPR-Cas9 screens to identify the cofactors used by nine different TFs and core promoters in human cells. Using this dataset, we associate TFs with cofactors, classify cofactors as ubiquitous or specific and discover transcriptional co-dependencies. Through a reductionistic, comparative approach, we demonstrate that TFs do not display discrete mechanisms of activation. Instead, each TF depends on a unique combination of cofactors, which influences distinct steps in transcription. By contrast, the influence of core promoters appears relatively discrete. Different promoter classes are constrained by either initiation or pause-release, which influences their dynamic range and compatibility with cofactors. Overall, our comparative cofactor screens characterize the interplay between TFs, cofactors and core promoters, identifying general principles by which they influence transcription.
    DOI:  https://doi.org/10.1038/s41588-024-01749-z
  12. Nat Cardiovasc Res. 2024 ;3(4): 441-459
    Histone H1.0 couples cellular mechanical behaviors to chromatin structure.
    Shuaishuai Hu, Douglas J Chapski, Natalie D Gehred, Todd H Kimball, Tatiana Gromova, Angelina Flores, Amy C Rowat, Junjie Chen, René R Sevag Packard, Emily Olszewski, Jennifer Davis, Christoph D Rau, Timothy A McKinsey, Manuel Rosa-Garrido, Thomas M Vondriska.
      Tuning of genome structure and function is accomplished by chromatin-binding proteins, which determine the transcriptome and phenotype of the cell. Here we investigate how communication between extracellular stress and chromatin structure may regulate cellular mechanical behaviors. We demonstrate that histone H1.0, which compacts nucleosomes into higher-order chromatin fibers, controls genome organization and cellular stress response. We show that histone H1.0 has privileged expression in fibroblasts across tissue types and that its expression is necessary and sufficient to induce myofibroblast activation. Depletion of histone H1.0 prevents cytokine-induced fibroblast contraction, proliferation and migration via inhibition of a transcriptome comprising extracellular matrix, cytoskeletal and contractile genes, through a process that involves locus-specific H3K27 acetylation. Transient depletion of histone H1.0 in vivo prevents fibrosis in cardiac muscle. These findings identify an unexpected role of linker histones to orchestrate cellular mechanical behaviors, directly coupling force generation, nuclear organization and gene transcription.
    Keywords:  Cardiovascular diseases; Cell biology; Histone post-translational modifications; Physiology
    DOI:  https://doi.org/10.1038/s44161-024-00460-w
  13. Genome Res. 2024 May 22. pii: gr.278565.123. [Epub ahead of print]
    Machine learning identifies activation of RUNX/AP-1 as drivers of mesenchymal and fibrotic regulatory programs in gastric cancer.
    Milad Razavi-Mohseni, Weitai Huang, Yu Amanda Guo, Dustin Shigaki, Shamaine Ho, Patrick Tan, Anders Skanderup, Michael A Beer.
      Gastric cancer (GC) is the fifth most common cancer worldwide and is a heterogeneous disease. Among GC subtypes, the mesenchymal phenotype (Mes-like) is more invasive than the epithelial phenotype (Epi-like). While gene expression of the epithelial-to-mesenchymal transition (EMT) has been studied, the regulatory landscape shaping this process is not fully understood. Here we use ATAC-seq and RNA-seq from a compendium of gastric cancer cell lines and primary tumors to detect drivers of regulatory state changes and their transcriptional responses. Using the ATAC-seq, we developed a machine learning approach to determine the transcription factors (TFs) regulating the subtypes of GC. We identified TFs driving the mesenchymal (RUNX2, ZEB1, SNAI2, AP-1 dimer) as well as the epithelial states (GATA4, GATA6, KLF5, HNF4A, FOXA2, GRHL2) in gastric cancer. We identified DNA copy number alterations associated with dysregulation of these TFs, specifically deletion of GATA4 and amplification of MAPK9 Comparisons with bulk and single-cell RNA-seq datasets identified activation toward fibroblast-like epigenomic and expression signatures in Mes-like GC. The activation of this mesenchymal fibrotic program is associated with differentially accessible DNA cis-regulatory elements flanking up-regulated mesenchymal genes. These findings establish a map of TF activity in GC and highlight the role of copy number driven alterations in shaping epigenomic regulatory programs as potential drivers of gastric cancer heterogeneity and progression.
    DOI:  https://doi.org/10.1101/gr.278565.123
  14. Nat Commun. 2024 May 22. 15(1): 4358
    DNA methylation-based high-resolution mapping of long-distance chromosomal interactions in nucleosome-depleted regions.
    Yi Li, James Lee, Lu Bai.
      3C-based methods have significantly advanced our understanding of 3D genome organization. However, it remains a formidable task to precisely capture long-range chromosomal interactions between individual loci, such as those between promoters and distal enhancers. Here, we present Methyltransferase Targeting-based chromosome Architecture Capture (MTAC), a method that maps the contacts between a target site (viewpoint) and the rest of the genome in budding yeast with high resolution and sensitivity. MTAC detects hundreds of intra- and inter-chromosomal interactions within nucleosome-depleted regions (NDRs) that cannot be captured by 4C, Hi-C, or Micro-C. By applying MTAC to various viewpoints, we find that (1) most long-distance chromosomal interactions detected by MTAC reflect tethering by the nuclear pore complexes (NPCs), (2) genes co-regulated by methionine assemble into inter-chromosomal clusters near NPCs upon activation, (3) mediated by condensin, the mating locus forms a highly specific interaction with the recombination enhancer (RE) in a mating-type specific manner, and (4) correlation of MTAC signals among NDRs reveal spatial mixing and segregation of the genome. Overall, these results demonstrate MTAC as a powerful tool to resolve fine-scale long-distance chromosomal interactions and provide insights into the 3D genome organization.
    DOI:  https://doi.org/10.1038/s41467-024-48718-y
  15. Nat Commun. 2024 May 21. 15(1): 4322
    The SUN-family protein Sad1 mediates heterochromatin spatial organization through interaction with histone H2A-H2B.
    Wenqi Sun, Qianhua Dong, Xueqing Li, Jinxin Gao, Xianwen Ye, Chunyi Hu, Fei Li, Yong Chen.
      Heterochromatin is generally associated with the nuclear periphery, but how the spatial organization of heterochromatin is regulated to ensure epigenetic silencing remains unclear. Here we found that Sad1, an inner nuclear membrane SUN-family protein in fission yeast, interacts with histone H2A-H2B but not H3-H4. We solved the crystal structure of the histone binding motif (HBM) of Sad1 in complex with H2A-H2B, revealing the intimate contacts between Sad1HBM and H2A-H2B. Structure-based mutagenesis studies revealed that the H2A-H2B-binding activity of Sad1 is required for the dynamic distribution of Sad1 throughout the nuclear envelope (NE). The Sad1-H2A-H2B complex mediates tethering telomeres and the mating-type locus to the NE. This complex is also important for heterochromatin silencing. Mechanistically, H2A-H2B enhances the interaction between Sad1 and HDACs, including Clr3 and Sir2, to maintain epigenetic identity of heterochromatin. Interestingly, our results suggest that Sad1 exhibits the histone-enhanced liquid-liquid phase separation property, which helps recruit heterochromatin factors to the NE. Our results uncover an unexpected role of SUN-family proteins in heterochromatin regulation and suggest a nucleosome-independent role of H2A-H2B in regulating Sad1's functionality.
    DOI:  https://doi.org/10.1038/s41467-024-48418-7
  16. Nat Commun. 2024 May 21. 15(1): 4325
    Cell of origin epigenetic priming determines susceptibility to Tet2 mutation.
    Giulia Schiroli, Vinay Kartha, Fabiana M Duarte, Trine A Kristiansen, Christina Mayerhofer, Rojesh Shrestha, Andrew Earl, Yan Hu, Tristan Tay, Catherine Rhee, Jason D Buenrostro, David T Scadden.
      Hematopoietic stem cell (HSC) mutations can result in clonal hematopoiesis (CH) with heterogeneous clinical outcomes. Here, we investigate how the cell state preceding Tet2 mutation impacts the pre-malignant phenotype. Using an inducible system for clonal analysis of myeloid progenitors, we find that the epigenetic features of clones at similar differentiation status are highly heterogeneous and functionally respond differently to Tet2 mutation. Cell differentiation stage also influences Tet2 mutation response indicating that the cell of origin's epigenome modulates clone-specific behaviors in CH. Molecular features associated with higher risk outcomes include Sox4 that sensitizes cells to Tet2 inactivation, inducing dedifferentiation, altered metabolism and increasing the in vivo clonal output of mutant cells, as confirmed in primary GMP and HSC models. Our findings validate the hypothesis that epigenetic features can predispose specific clones for dominance, explaining why identical genetic mutations can result in different phenotypes.
    DOI:  https://doi.org/10.1038/s41467-024-48508-6
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