bims-crepig Biomed News
on Chromatin regulation and epigenetics in cell fate and cancer
Issue of 2024‒09‒08
23 papers selected by
Connor Rogerson, University of Cambridge
  1. Histone H3.3 lysine 9 and 27 control repressive chromatin at cryptic enhancers and bivalent promoters.
  2. Genome access is transcription factor-specific and defined by nucleosome position.
  3. Identification of transcription factor co-binding patterns with non-negative matrix factorization.
  4. Enhlink infers distal and context-specific enhancer-promoter linkages.
  5. PICKLE-mediated nucleosome condensing drives H3K27me3 spreading for the inheritance of Polycomb memory during differentiation.
  6. Genome binding properties of Zic transcription factors underlie their changing functions during neuronal maturation.
  7. Single-cell chromatin accessibility reveals malignant regulatory programs in primary human cancers.
  8. Smarcd1 subunit of SWI/SNF chromatin-remodeling complexes collaborates with E2a to promote murine lymphoid specification.
  9. DNA methylation controls stemness of astrocytes in health and ischaemia.
  10. The scaffolding function of LSD1 controls DNA methylation in mouse ESCs.
  11. YY1-controlled regulatory connectivity and transcription are influenced by the cell cycle.
  12. Phosphorylation activates master growth regulator DELLA by promoting histone H2A binding at chromatin in Arabidopsis.
  13. Single-molecule imaging of SWI/SNF chromatin remodelers reveals bromodomain-mediated and cancer-mutants-specific landscape of multi-modal DNA-binding dynamics.
  14. SnapHiC-G: identifying long-range enhancer-promoter interactions from single-cell Hi-C data via a global background model.
  15. DNA methylation governs the sensitivity of repeats to restriction by the HUSH-MORC2 corepressor.
  16. MOF-mediated PRDX1 acetylation regulates inflammatory macrophage activation.
  17. Extracting regulatory active chromatin footprint from cell-free DNA.
  18. 5-Formylcytosine is an activating epigenetic mark for RNA Pol III during zygotic reprogramming.
  19. Improved simultaneous mapping of epigenetic features and 3D chromatin structure via ViCAR.
  20. A non-canonical repressor function of JUN restrains YAP activity and liver cancer growth.
  21. Multi-omic lineage tracing predicts the transcriptional, epigenetic and genetic determinants of cancer evolution.
  22. A comparative analysis of ENCODE and Cistrome in the context of TF binding signal.
  23. Stabilization of the hexasome intermediate during histone exchange by yeast SWR1 complex.
  1. Nat Commun. 2024 Aug 30. 15(1): 7557
    Histone H3.3 lysine 9 and 27 control repressive chromatin at cryptic enhancers and bivalent promoters.
    Matteo Trovato, Daria Bunina, Umut Yildiz, Nadine Fernandez-Novel Marx, Michael Uckelmann, Vita Levina, Yekaterina Perez, Ana Janeva, Benjamin A Garcia, Chen Davidovich, Judith B Zaugg, Kyung-Min Noh.
      Histone modifications are associated with distinct transcriptional states, but it is unclear whether they instruct gene expression. To investigate this, we mutate histone H3.3 K9 and K27 residues in mouse embryonic stem cells (mESCs). Here, we find that H3.3K9 is essential for controlling specific distal intergenic regions and for proper H3K27me3 deposition at promoters. The H3.3K9A mutation resulted in decreased H3K9me3 at regions encompassing endogenous retroviruses and induced a gain of H3K27ac and nascent transcription. These changes in the chromatin environment unleash cryptic enhancers, resulting in the activation of distinctive transcriptional programs and culminating in protein expression normally restricted to specialized immune cell types. The H3.3K27A mutant disrupts the deposition and spreading of the repressive H3K27me3 mark, particularly impacting bivalent genes with higher basal levels of H3.3 at promoters. Therefore, H3.3K9 and K27 crucially orchestrate repressive chromatin states at cis-regulatory elements and bivalent promoters, respectively, and instruct proper transcription in mESCs.
    DOI:  https://doi.org/10.1038/s41467-024-51785-w
  2. Mol Cell. 2024 Aug 22. pii: S1097-2765(24)00663-4. [Epub ahead of print]
    Genome access is transcription factor-specific and defined by nucleosome position.
    Ralph Stefan Grand, Marco Pregnolato, Lisa Baumgartner, Leslie Hoerner, Lukas Burger, Dirk Schübeler.
      Mammalian gene expression is controlled by transcription factors (TFs) that engage sequence motifs in a chromatinized genome, where nucleosomes can restrict DNA access. Yet, how nucleosomes affect individual TFs remains unclear. Here, we measure the ability of over one hundred TF motifs to recruit TFs in a defined chromosomal locus in mouse embryonic stem cells. This identifies a set sufficient to enable the binding of TFs with diverse tissue specificities, functions, and DNA-binding domains. These chromatin-competent factors are further classified when challenged to engage motifs within a highly phased nucleosome. The pluripotency factors OCT4-SOX2 preferentially engage non-nucleosomal and entry-exit motifs, but not nucleosome-internal sites, a preference that also guides binding genome wide. By contrast, factors such as BANP, REST, or CTCF engage throughout, causing nucleosomal displacement. This supports that TFs vary widely in their sensitivity to nucleosomes and that genome access is TF specific and influenced by nucleosome position in the cell.
    Keywords:  accessibility; chromatin; genome; nucleosome; pioneer factors; transcription factors
    DOI:  https://doi.org/10.1016/j.molcel.2024.08.009
  3. Nucleic Acids Res. 2024 Sep 01. pii: gkae743. [Epub ahead of print]
    Identification of transcription factor co-binding patterns with non-negative matrix factorization.
    Ieva Rauluseviciute, Timothée Launay, Guido Barzaghi, Sarvesh Nikumbh, Boris Lenhard, Arnaud Regis Krebs, Jaime A Castro-Mondragon, Anthony Mathelier.
      Transcription factor (TF) binding to DNA is critical to transcription regulation. Although the binding properties of numerous individual TFs are well-documented, a more detailed comprehension of how TFs interact cooperatively with DNA is required. We present COBIND, a novel method based on non-negative matrix factorization (NMF) to identify TF co-binding patterns automatically. COBIND applies NMF to one-hot encoded regions flanking known TF binding sites (TFBSs) to pinpoint enriched DNA patterns at fixed distances. We applied COBIND to 5699 TFBS datasets from UniBind for 401 TFs in seven species. The method uncovered already established co-binding patterns and new co-binding configurations not yet reported in the literature and inferred through motif similarity and protein-protein interaction knowledge. Our extensive analyses across species revealed that 67% of the TFs shared a co-binding motif with other TFs from the same structural family. The co-binding patterns captured by COBIND are likely functionally relevant as they harbor higher evolutionarily conservation than isolated TFBSs. Open chromatin data from matching human cell lines further supported the co-binding predictions. Finally, we used single-molecule footprinting data from mouse embryonic stem cells to confirm that the COBIND-predicted co-binding events associated with some TFs likely occurred on the same DNA molecules.
    DOI:  https://doi.org/10.1093/nar/gkae743
  4. Genome Biol. 2024 Sep 02. 25(1): 235
    Enhlink infers distal and context-specific enhancer-promoter linkages.
    Olivier B Poirion, Wulin Zuo, Catrina Spruce, Candice N Baker, Sandra L Daigle, Ashley Olson, Daniel A Skelly, Elissa J Chesler, Christopher L Baker, Brian S White.
      Enhlink is a computational tool for scATAC-seq data analysis, facilitating precise interrogation of enhancer function at the single-cell level. It employs an ensemble approach incorporating technical and biological covariates to infer condition-specific regulatory DNA linkages. Enhlink can integrate multi-omic data for enhanced specificity, when available. Evaluation with simulated and real data, including multi-omic datasets from the mouse striatum and novel promoter capture Hi-C data, demonstrate that Enhlink outperfoms alternative methods. Coupled with eQTL analysis, it identified a putative super-enhancer in striatal neurons. Overall, Enhlink offers accuracy, power, and potential for revealing novel biological insights in gene regulation.
    Keywords:  Chromatin accessibility; Enhancers inference; Linkage analysis; Machine-learning; Single-cell
    DOI:  https://doi.org/10.1186/s13059-024-03374-9
  5. Mol Cell. 2024 Aug 30. pii: S1097-2765(24)00692-0. [Epub ahead of print]
    PICKLE-mediated nucleosome condensing drives H3K27me3 spreading for the inheritance of Polycomb memory during differentiation.
    Zhenwei Liang, Tao Zhu, Yaoguang Yu, Caihong Wu, Yisui Huang, Yuanhao Hao, Xin Song, Wei Fu, Liangbing Yuan, Yuhai Cui, Shangzhi Huang, Chenlong Li.
      Spreading of H3K27me3 is crucial for the maintenance of mitotically inheritable Polycomb-mediated chromatin silencing in animals and plants. However, how Polycomb repressive complex 2 (PRC2) accesses unmodified nucleosomes in spreading regions for spreading H3K27me3 remains unclear. Here, we show in Arabidopsis thaliana that the chromatin remodeler PICKLE (PKL) plays a specialized role in H3K27me3 spreading to safeguard cell identity during differentiation. PKL specifically localizes to H3K27me3 spreading regions but not to nucleation sites and physically associates with PRC2. Loss of PKL disrupts the occupancy of the PRC2 catalytic subunit CLF in spreading regions and leads to aberrant dedifferentiation. Nucleosome density increase endowed by the ATPase function of PKL ensures that unmodified nucleosomes are accessible to PRC2 catalytic activity for H3K27me3 spreading. Our findings demonstrate that PKL-dependent nucleosome compaction is critical for PRC2-mediated H3K27me3 read-and-write function in H3K27me3 spreading, thus revealing a mechanism by which repressive chromatin domains are established and propagated.
    Keywords:  Arabidopsis; H3K27me3 spreading; LEC2; PICKLE; Polycomb silencing memory; chromatin remodeling; differentiation; nucleosome condensing; seed germination
    DOI:  https://doi.org/10.1016/j.molcel.2024.08.018
  6. BMC Biol. 2024 Sep 02. 22(1): 189
    Genome binding properties of Zic transcription factors underlie their changing functions during neuronal maturation.
    Melyssa S Minto, Jesús Emiliano Sotelo-Fonseca, Vijyendra Ramesh, Anne E West.
      BACKGROUND: The Zic family of transcription factors (TFs) promote both proliferation and maturation of cerebellar granule neurons (CGNs), raising the question of how a single, constitutively expressed TF family can support distinct developmental processes. Here we use an integrative experimental and bioinformatic approach to discover the regulatory relationship between Zic TF binding and changing programs of gene transcription during postnatal CGN differentiation.RESULTS: We first established a bioinformatic pipeline to integrate Zic ChIP-seq data from the developing mouse cerebellum with other genomic datasets from the same tissue. In newborn CGNs, Zic TF binding predominates at active enhancers that are co-bound by developmentally regulated TFs including Atoh1, whereas in mature CGNs, Zic TF binding consolidates toward promoters where it co-localizes with activity-regulated TFs. We then performed CUT&RUN-seq in differentiating CGNs to define both the time course of developmental shifts in Zic TF binding and their relationship to gene expression. Mapping Zic TF binding sites to genes using chromatin looping, we identified the set of Zic target genes that have altered expression in RNA-seq from Zic1 or Zic2 knockdown CGNs.
    CONCLUSIONS: Our data show that Zic TFs are required for both induction and repression of distinct, developmentally regulated target genes through a mechanism that is largely independent of changes in Zic TF binding. We suggest that the differential collaboration of Zic TFs with other TF families underlies the shift in their biological functions across CGN development.
    Keywords:  Bioinformatic analyses; Cerebellar granule neuron maturation; Developmental gene expression; Genome binding dynamics; Transcription factor collaboration; Zic transcription factors
    DOI:  https://doi.org/10.1186/s12915-024-01989-9
  7. Science. 2024 Sep 06. 385(6713): eadk9217
    Single-cell chromatin accessibility reveals malignant regulatory programs in primary human cancers.
    Cancer Genome Atlas Analysis Network‡
      To identify cancer-associated gene regulatory changes, we generated single-cell chromatin accessibility landscapes across eight tumor types as part of The Cancer Genome Atlas. Tumor chromatin accessibility is strongly influenced by copy number alterations that can be used to identify subclones, yet underlying cis-regulatory landscapes retain cancer type-specific features. Using organ-matched healthy tissues, we identified the "nearest healthy" cell types in diverse cancers, demonstrating that the chromatin signature of basal-like-subtype breast cancer is most similar to secretory-type luminal epithelial cells. Neural network models trained to learn regulatory programs in cancer revealed enrichment of model-prioritized somatic noncoding mutations near cancer-associated genes, suggesting that dispersed, nonrecurrent, noncoding mutations in cancer are functional. Overall, these data and interpretable gene regulatory models for cancer and healthy tissue provide a framework for understanding cancer-specific gene regulation.
    DOI:  https://doi.org/10.1126/science.adk9217
  8. Dev Cell. 2024 Aug 30. pii: S1534-5807(24)00490-8. [Epub ahead of print]
    Smarcd1 subunit of SWI/SNF chromatin-remodeling complexes collaborates with E2a to promote murine lymphoid specification.
    Pierre Priam, Veneta Krasteva, Philippe Rousseau, Alexandre Polsinelli, Laurence Côté, Ines Desanlis, Azer Farah, Vincent-Philippe Lavallée, Marie Kmita, Julie A Lessard.
      Lymphocyte development from murine hematopoietic stem cells (HSCs) entails a loss of self-renewal capacity and a progressive restriction of developmental potential. Previous research from our laboratory suggests that specialized assemblies of ATP-dependent SWI/SNF chromatin-remodeling complexes play lineage-specific roles during murine hematopoiesis. Here, we demonstrate that the Smarcd1 subunit is essential for specification of lymphoid cell fate from multipotent progenitors. Acute deletion of Smarcd1 in murine adult hematopoiesis leads to lymphopenia, characterized by a near-complete absence of early lymphoid progenitors and mature B and T cells, while the myeloid and erythroid lineages remain unaffected. Mechanistically, we demonstrate that Smarcd1 is essential for the coordinated activation of a lymphoid gene signature in murine multipotent progenitors. This is achieved by interacting with the E2a transcription factor at proximal promoters and by regulating the activity of distal enhancers. Globally, these findings identify Smarcd1 as an essential chromatin remodeler that governs lymphoid cell fate.
    Keywords:  E2a/Tcf3; SWI/SNF complexes; Smarcd1/BAF60a; active enhancers; chromatin remodeling; lymphoid priming; lymphopenia
    DOI:  https://doi.org/10.1016/j.devcel.2024.08.007
  9. Nature. 2024 Sep 04.
    DNA methylation controls stemness of astrocytes in health and ischaemia.
    Lukas P M Kremer, Santiago Cerrizuela, Hadil El-Sammak, Mohammad Eid Al Shukairi, Tobias Ellinger, Jannes Straub, Aylin Korkmaz, Katrin Volk, Jan Brunken, Susanne Kleber, Simon Anders, Ana Martin-Villalba.
      Astrocytes are the most abundant cell type in the mammalian brain and provide structural and metabolic support to neurons, regulate synapses and become reactive after injury and disease. However, a small subset of astrocytes settles in specialized areas of the adult brain where these astrocytes instead actively generate differentiated neuronal and glial progeny and are therefore referred to as neural stem cells1-3. Common parenchymal astrocytes and quiescent neural stem cells share similar transcriptomes despite their very distinct functions4-6. Thus, how stem cell activity is molecularly encoded remains unknown. Here we examine the transcriptome, chromatin accessibility and methylome of neural stem cells and their progeny, and of astrocytes from the striatum and cortex in the healthy and ischaemic adult mouse brain. We identify distinct methylation profiles associated with either astrocyte or stem cell function. Stem cell function is mediated by methylation of astrocyte genes and demethylation of stem cell genes that are expressed later. Ischaemic injury to the brain induces gain of stemness in striatal astrocytes7. We show that this response involves reprogramming the astrocyte methylome to a stem cell methylome and is absent if the de novo methyltransferase DNMT3A is missing. Overall, we unveil DNA methylation as a promising target for regenerative medicine.
    DOI:  https://doi.org/10.1038/s41586-024-07898-9
  10. Nat Commun. 2024 Sep 05. 15(1): 7758
    The scaffolding function of LSD1 controls DNA methylation in mouse ESCs.
    Sandhya Malla, Kanchan Kumari, Carlos A García-Prieto, Jonatan Caroli, Anna Nordin, Trinh T T Phan, Devi Prasad Bhattarai, Carlos Martinez-Gamero, Eshagh Dorafshan, Stephanie Stransky, Damiana Álvarez-Errico, Paulina Avovome Saiki, Weiyi Lai, Cong Lyu, Ludvig Lizana, Jonathan D Gilthorpe, Hailin Wang, Simone Sidoli, Andre Mateus, Dung-Fang Lee, Claudio Cantù, Manel Esteller, Andrea Mattevi, Angel-Carlos Roman, Francesca Aguilo.
      Lysine-specific histone demethylase 1 (LSD1), which demethylates mono- or di- methylated histone H3 on lysine 4 (H3K4me1/2), is essential for early embryogenesis and development. Here we show that LSD1 is dispensable for mouse embryonic stem cell (ESC) self-renewal but is required for mouse ESC growth and differentiation. Reintroduction of a catalytically-impaired LSD1 (LSD1MUT) recovers the proliferation capability of mouse ESCs, yet the enzymatic activity of LSD1 is essential to ensure proper differentiation. Indeed, increased H3K4me1 in Lsd1 knockout (KO) mouse ESCs does not lead to major changes in global gene expression programs related to stemness. However, ablation of LSD1 but not LSD1MUT results in decreased DNMT1 and UHRF1 proteins coupled to global hypomethylation. We show that both LSD1 and LSD1MUT control protein stability of UHRF1 and DNMT1 through interaction with HDAC1 and the ubiquitin-specific peptidase 7 (USP7), consequently, facilitating the deacetylation and deubiquitination of DNMT1 and UHRF1. Our studies elucidate a mechanism by which LSD1 controls DNA methylation in mouse ESCs, independently of its lysine demethylase activity.
    DOI:  https://doi.org/10.1038/s41467-024-51966-7
  11. Nat Genet. 2024 Aug 29.
    YY1-controlled regulatory connectivity and transcription are influenced by the cell cycle.
    Jessica C Lam, Nicholas G Aboreden, Susannah C Midla, Siqing Wang, Anran Huang, Cheryl A Keller, Belinda Giardine, Kate A Henderson, Ross C Hardison, Haoyue Zhang, Gerd A Blobel.
      Few transcription factors have been examined for their direct roles in physically connecting enhancers and promoters. Here acute degradation of Yin Yang 1 (YY1) in erythroid cells revealed its requirement for the maintenance of numerous enhancer-promoter loops, but not compartments or domains. Despite its reported ability to interact with cohesin, the formation of YY1-dependent enhancer-promoter loops does not involve stalling of cohesin-mediated loop extrusion. Integrating mitosis-to-G1-phase dynamics, we observed partial retention of YY1 on mitotic chromatin, predominantly at gene promoters, followed by rapid rebinding during mitotic exit, coinciding with enhancer-promoter loop establishment. YY1 degradation during the mitosis-to-G1-phase interval revealed a set of enhancer-promoter loops that require YY1 for establishment during G1-phase entry but not for maintenance in interphase, suggesting that cell cycle stage influences YY1's architectural function. Thus, as revealed here for YY1, chromatin architectural functions of transcription factors can vary in their interplay with CTCF and cohesin as well as by cell cycle stage.
    DOI:  https://doi.org/10.1038/s41588-024-01871-y
  12. Nat Commun. 2024 Sep 03. 15(1): 7694
    Phosphorylation activates master growth regulator DELLA by promoting histone H2A binding at chromatin in Arabidopsis.
    Xu Huang, Rodolfo Zentella, Jeongmoo Park, Larry Reser, Dina L Bai, Mark M Ross, Jeffrey Shabanowitz, Donald F Hunt, Tai-Ping Sun.
      DELLA proteins are conserved master growth regulators that play a central role in controlling plant development in response to internal and environmental cues. DELLAs function as transcription regulators, which are recruited to target promoters by binding to transcription factors (TFs) and histone H2A via their GRAS domain. Recent studies showed that DELLA stability is regulated post-translationally via two mechanisms, phytohormone gibberellin-induced polyubiquitination for its rapid degradation, and Small Ubiquitin-like Modifier (SUMO)-conjugation to increase its accumulation. Moreover, DELLA activity is dynamically modulated by two distinct glycosylations: DELLA-TF interactions are enhanced by O-fucosylation, but inhibited by O-linked N-acetylglucosamine (O-GlcNAc) modification. However, the role of DELLA phosphorylation remains unclear as previous studies showing conflicting results ranging from findings that suggest phosphorylation promotes or reduces DELLA degradation to others indicating it has no effect on its stability. Here, we identify phosphorylation sites in REPRESSOR OF ga1-3 (RGA, an AtDELLA) purified from Arabidopsis by mass spectrometry analysis, and show that phosphorylation of two RGA peptides in the PolyS and PolyS/T regions enhances RGA activity by promoting H2A binding and RGA association with target promoters. Notably, phosphorylation does not affect RGA-TF interactions or RGA stability. Our study has uncovered a molecular mechanism of phosphorylation-induced DELLA activity.
    DOI:  https://doi.org/10.1038/s41467-024-52033-x
  13. Nat Commun. 2024 Sep 02. 15(1): 7646
    Single-molecule imaging of SWI/SNF chromatin remodelers reveals bromodomain-mediated and cancer-mutants-specific landscape of multi-modal DNA-binding dynamics.
    Wilfried Engl, Aliz Kunstar-Thomas, Siyi Chen, Woei Shyuan Ng, Hendrik Sielaff, Ziqing Winston Zhao.
      Despite their prevalent cancer implications, the in vivo dynamics of SWI/SNF chromatin remodelers and how misregulation of such dynamics underpins cancer remain poorly understood. Using live-cell single-molecule tracking, we quantify the intranuclear diffusion and chromatin-binding of three key subunits common to all major human SWI/SNF remodeler complexes (BAF57, BAF155 and BRG1), and resolve two temporally distinct stable binding modes for the fully assembled complex. Super-resolved density mapping reveals heterogeneous, nanoscale remodeler binding "hotspots" across the nucleoplasm where multiple binding events (especially longer-lived ones) preferentially cluster. Importantly, we uncover distinct roles of the bromodomain in modulating chromatin binding/targeting in a DNA-accessibility-dependent manner, pointing to a model where successive longer-lived binding within "hotspots" leads to sustained productive remodeling. Finally, systematic comparison of six common BRG1 mutants implicated in various cancers unveils alterations in chromatin-binding dynamics unique to each mutant, shedding insight into a multi-modal landscape regulating the spatio-temporal organizational dynamics of SWI/SNF remodelers.
    DOI:  https://doi.org/10.1038/s41467-024-52040-y
  14. Brief Bioinform. 2024 Jul 25. pii: bbae426. [Epub ahead of print]25(5):
    SnapHiC-G: identifying long-range enhancer-promoter interactions from single-cell Hi-C data via a global background model.
    Weifang Liu, Wujuan Zhong, Paola Giusti-Rodríguez, Zhiyun Jiang, Geoffery W Wang, Huaigu Sun, Ming Hu, Yun Li.
      Harnessing the power of single-cell genomics technologies, single-cell Hi-C (scHi-C) and its derived technologies provide powerful tools to measure spatial proximity between regulatory elements and their target genes in individual cells. Using a global background model, we propose SnapHiC-G, a computational method, to identify long-range enhancer-promoter interactions from scHi-C data. We applied SnapHiC-G to scHi-C datasets generated from mouse embryonic stem cells and human brain cortical cells. SnapHiC-G achieved high sensitivity in identifying long-range enhancer-promoter interactions. Moreover, SnapHiC-G can identify putative target genes for noncoding genome-wide association study (GWAS) variants, and the genetic heritability of neuropsychiatric diseases is enriched for single-nucleotide polymorphisms (SNPs) within SnapHiC-G-identified interactions in a cell-type-specific manner. In sum, SnapHiC-G is a powerful tool for characterizing cell-type-specific enhancer-promoter interactions from complex tissues and can facilitate the discovery of chromatin interactions important for gene regulation in biologically relevant cell types.
    Keywords:  GWAS; Hi-C; enhancer–promoter interactions; epigenetics; single cell
    DOI:  https://doi.org/10.1093/bib/bbae426
  15. Nat Commun. 2024 Aug 30. 15(1): 7534
    DNA methylation governs the sensitivity of repeats to restriction by the HUSH-MORC2 corepressor.
    Ninoslav Pandiloski, Vivien Horváth, Ofelia Karlsson, Symela Koutounidou, Fereshteh Dorazehi, Georgia Christoforidou, Jon Matas-Fuentes, Patricia Gerdes, Raquel Garza, Marie E Jönsson, Anita Adami, Diahann A M Atacho, Jenny G Johansson, Elisabet Englund, Zaal Kokaia, Johan Jakobsson, Christopher H Douse.
      The human silencing hub (HUSH) complex binds to transcripts of LINE-1 retrotransposons (L1s) and other genomic repeats, recruiting MORC2 and other effectors to remodel chromatin. How HUSH and MORC2 operate alongside DNA methylation, a central epigenetic regulator of repeat transcription, remains largely unknown. Here we interrogate this relationship in human neural progenitor cells (hNPCs), a somatic model of brain development that tolerates removal of DNA methyltransferase DNMT1. Upon loss of MORC2 or HUSH subunit TASOR in hNPCs, L1s remain silenced by robust promoter methylation. However, genome demethylation and activation of evolutionarily-young L1s attracts MORC2 binding, and simultaneous depletion of DNMT1 and MORC2 causes massive accumulation of L1 transcripts. We identify the same mechanistic hierarchy at pericentromeric α-satellites and clustered protocadherin genes, repetitive elements important for chromosome structure and neurodevelopment respectively. Our data delineate the epigenetic control of repeats in somatic cells, with implications for understanding the vital functions of HUSH-MORC2 in hypomethylated contexts throughout human development.
    DOI:  https://doi.org/10.1038/s41467-024-50765-4
  16. Cell Rep. 2024 Aug 28. pii: S2211-1247(24)01033-7. [Epub ahead of print]43(9): 114682
    MOF-mediated PRDX1 acetylation regulates inflammatory macrophage activation.
    Hui-Ru Chen, Yidan Sun, Gerhard Mittler, Tobias Rumpf, Maria Shvedunova, Rudolf Grosschedl, Asifa Akhtar.
      Signaling-dependent changes in protein phosphorylation are critical to enable coordination of transcription and metabolism during macrophage activation. However, the role of acetylation in signal transduction during macrophage activation remains obscure. Here, we identify the redox signaling regulator peroxiredoxin 1 (PRDX1) as a substrate of the lysine acetyltransferase MOF. MOF acetylates PRDX1 at lysine 197, preventing hyperoxidation and thus maintaining its activity under stress. PRDX1 K197ac responds to inflammatory signals, decreasing rapidly in mouse macrophages stimulated with bacterial lipopolysaccharides (LPSs) but not with interleukin (IL)-4 or IL-10. The LPS-induced decrease of PRDX1 K197ac elevates cellular hydrogen peroxide accumulation and augments ERK1/2, but not p38 or AKT, phosphorylation. Concomitantly, diminished PRDX1 K197ac stimulates glycolysis, potentiates H3 serine 28 phosphorylation, and ultimately enhances the production of pro-inflammatory mediators such as IL-6. Our work reveals a regulatory role for redox protein acetylation in signal transduction and coordinating metabolic and transcriptional programs during inflammatory macrophage activation.
    Keywords:  CP: Immunology; CP: Molecular biology; ERK1/2; MAPK; glycolytic metabolism; histone H3 serine 28 phosphorylation; lysine acetyltransferase MOF; macrophage activation; peroxiredoxin; protein acetylation; redox signaling; signal transduction
    DOI:  https://doi.org/10.1016/j.celrep.2024.114682
  17. Commun Biol. 2024 Sep 04. 7(1): 1086
    Extracting regulatory active chromatin footprint from cell-free DNA.
    Kevin Lai, Katharine Dilger, Rachael Cunningham, Kathy T Lam, Rhea Boquiren, Khiet Truong, Maggie C Louie, Richard Rava, Diana Abdueva.
      Cell-free DNA (cfDNA) has emerged as a pivotal player in precision medicine, revolutionizing the diagnostic and therapeutic landscape. While its clinical applications have significantly increased in recent years, current cfDNA assays have limited ability to identify the active transcriptional programs that govern complex disease phenotypes and capture the heterogeneity of the disease. To address these limitations, we have developed a non-invasive platform to enrich and examine the active chromatin fragments (cfDNAac) in peripheral blood. The deconvolution of the cfDNAac signal from traditional nucleosomal chromatin fragments (cfDNAnuc) yields a catalog of features linking these circulating chromatin signals in blood to specific regulatory elements across the genome, including enhancers, promoters, and highly transcribed genes, mirroring the epigenetic data from the ENCODE project. Notably, these cfDNAac counts correlate strongly with RNA polymerase II activity and exhibit distinct expression patterns for known circadian genes. Additionally, cfDNAac signals across gene bodies and promoters show strong correlations with whole blood gene expression levels defined by GTEx. This study illustrates the utility of cfDNAac analysis for investigating epigenomics and gene expression, underscoring its potential for a wide range of clinical applications in precision medicine.
    DOI:  https://doi.org/10.1038/s42003-024-06769-3
  18. Cell. 2024 Aug 28. pii: S0092-8674(24)00902-4. [Epub ahead of print]
    5-Formylcytosine is an activating epigenetic mark for RNA Pol III during zygotic reprogramming.
    Eleftheria Parasyraki, Medhavi Mallick, Victoria Hatch, Viviana Vastolo, Michael U Musheev, Emil Karaulanov, Alexandr Gopanenko, Simon Moxon, Maria Méndez-Lago, Dandan Han, Lars Schomacher, Debasish Mukherjee, Christof Niehrs.
      5-Methylcytosine (5mC) is an established epigenetic mark in vertebrate genomic DNA, but whether its oxidation intermediates formed during TET-mediated DNA demethylation possess an instructive role of their own that is also physiologically relevant remains unresolved. Here, we reveal a 5-formylcytosine (5fC) nuclear chromocenter, which transiently forms during zygotic genome activation (ZGA) in Xenopus and mouse embryos. We identify this chromocenter as the perinucleolar compartment, a structure associated with RNA Pol III transcription. In Xenopus embryos, 5fC is highly enriched on Pol III target genes activated at ZGA, notably at oocyte-type tandem arrayed tRNA genes. By manipulating Tet and Tdg enzymes, we show that 5fC is required as a regulatory mark to promote Pol III recruitment as well as tRNA expression. Concordantly, 5fC modification of a tRNA transgene enhances its expression in vivo. The results establish 5fC as an activating epigenetic mark during zygotic reprogramming of Pol III gene expression.
    Keywords:  5-formylcytosine; B-box; RNA Pol III; TDG; TET; Xenopus; ZGA; perinucleolar compartment; tRNA; tRNA-iMet
    DOI:  https://doi.org/10.1016/j.cell.2024.08.011
  19. Genome Biol. 2024 Sep 03. 25(1): 237
    Improved simultaneous mapping of epigenetic features and 3D chromatin structure via ViCAR.
    Sean M Flynn, Somdutta Dhir, Krzysztof Herka, Colm Doyle, Larry Melidis, Angela Simeone, Winnie W I Hui, Rafael de Cesaris Araujo Tavares, Stefan Schoenfelder, David Tannahill, Shankar Balasubramanian.
      Methods to measure chromatin contacts at genomic regions bound by histone modifications or proteins are important tools to investigate chromatin organization. However, such methods do not capture the possible involvement of other epigenomic features such as G-quadruplex DNA secondary structures (G4s). To bridge this gap, we introduce ViCAR (viewpoint HiCAR), for the direct antibody-based capture of chromatin interactions at folded G4s. Through ViCAR, we showcase the first G4-3D interaction landscape. Using histone marks, we also demonstrate how ViCAR improves on earlier approaches yielding increased signal-to-noise. ViCAR is a practical and powerful tool to explore epigenetic marks and 3D genome interactomes.
    Keywords:  3D genome structure; G-quadruplex DNA; Hi-C; Histone marks
    DOI:  https://doi.org/10.1186/s13059-024-03377-6
  20. EMBO J. 2024 Aug 29.
    A non-canonical repressor function of JUN restrains YAP activity and liver cancer growth.
    Yuliya Kurlishchuk, Anita Cindric Vranesic, Marco Jessen, Alexandra Kipping, Christin Ritter, KyungMok Kim, Paul Cramer, Björn von Eyss.
      Yes-associated protein (YAP) and its homolog, transcriptional coactivator with PDZ-binding motif (TAZ), are the main transcriptional downstream effectors of the Hippo pathway. Decreased Hippo pathway activity leads to nuclear translocation of YAP/TAZ where they interact with TEAD transcription factors to induce target gene expression. Unrestrained YAP/TAZ activity can lead to excessive growth and tumor formation in a short time, underscoring the evolutionary need for tight control of these two transcriptional coactivators. Here, we report that the AP-1 component JUN acts as specific repressor of YAP/TAZ at joint target sites to decrease YAP/TAZ activity. This function of JUN is independent of its heterodimeric AP-1 partner FOS and the canonical AP-1 function. Since expression of JUN is itself induced by YAP/TAZ, our work identifies a JUN-dependent negative feedback loop that buffers YAP/TAZ activity at joint genomic sites. This negative feedback loop gets disrupted in liver cancer to unlock the full oncogenic potential of YAP/TAZ. Our results thus demonstrate an additional layer of control for the interplay of YAP/TAZ and AP-1.
    Keywords:  AP-1; Hippo; JUN; Liver Cancer; YAP
    DOI:  https://doi.org/10.1038/s44318-024-00188-0
  21. Nat Commun. 2024 Sep 01. 15(1): 7609
    Multi-omic lineage tracing predicts the transcriptional, epigenetic and genetic determinants of cancer evolution.
    F Nadalin, M J Marzi, M Pirra Piscazzi, P Fuentes-Bravo, S Procaccia, M Climent, P Bonetti, C Rubolino, B Giuliani, I Papatheodorou, J C Marioni, F Nicassio.
      Cancer is a highly heterogeneous disease, where phenotypically distinct subpopulations coexist and can be primed to different fates. Both genetic and epigenetic factors may drive cancer evolution, however little is known about whether and how such a process is pre-encoded in cancer clones. Using single-cell multi-omic lineage tracing and phenotypic assays, we investigate the predictive features of either tumour initiation or drug tolerance within the same cancer population. Clones primed to tumour initiation in vivo display two distinct transcriptional states at baseline. Remarkably, these states share a distinctive DNA accessibility profile, highlighting an epigenetic basis for tumour initiation. The drug tolerant niche is also largely pre-encoded, but only partially overlaps the tumour-initiating one and evolves following two genetically and transcriptionally distinct trajectories. Our study highlights coexisting genetic, epigenetic and transcriptional determinants of cancer evolution, unravelling the molecular complexity of pre-encoded tumour phenotypes.
    DOI:  https://doi.org/10.1038/s41467-024-51424-4
  22. BMC Genomics. 2024 Aug 30. 25(Suppl 3): 817
    A comparative analysis of ENCODE and Cistrome in the context of TF binding signal.
    Stefano Perna, Pietro Pinoli, Stefano Ceri, Limsoon Wong.
      BACKGROUND: With the rise of publicly available genomic data repositories, it is now common for scientists to rely on computational models and preprocessed data, either as control or to discover new knowledge. However, different repositories adhere to the different principles and guidelines, and data processing plays a significant role in the quality of the resulting datasets. Two popular repositories for transcription factor binding sites data - ENCODE and Cistrome - process the same biological samples in alternative ways, and their results are not always consistent. Moreover, the output format of the processing (BED narrowPeak) exposes a feature, the signalValue, which is seldom used in consistency checks, but can offer valuable insight on the quality of the data.RESULTS: We provide evidence that data points with high signalValue(s) (top 25% of values) are more likely to be consistent between ENCODE and Cistrome in human cell lines K562, GM12878, and HepG2. In addition, we show that filtering according to said high values improves the quality of predictions for a machine learning algorithm that detects transcription factor interactions based only on positional information. Finally, we provide a set of practices and guidelines, based on the signalValue feature, for scientists who wish to compare and merge narrowPeaks from ENCODE and Cistrome.
    CONCLUSIONS: The signalValue feature is an informative feature that can be effectively used to highlight consistent areas of overlap between different sources of TF binding sites that expose it. Its applicability extends to downstream to positional machine learning algorithms, making it a powerful tool for performance tweaking and data aggregation.
    Keywords:  Cistrome; Database; ENCODE; SignalValue; Transcription Factors
    DOI:  https://doi.org/10.1186/s12864-024-10668-6
  23. Mol Cell. 2024 Aug 28. pii: S1097-2765(24)00669-5. [Epub ahead of print]
    Stabilization of the hexasome intermediate during histone exchange by yeast SWR1 complex.
    Adam S B Jalal, Paul Girvan, Eugene Y D Chua, Lexin Liu, Shijie Wang, Elizabeth A McCormack, Michael T Skehan, Carol L Knight, David S Rueda, Dale B Wigley.
      The yeast SWR1 complex catalyzes the exchange of histone H2A/H2B dimers in nucleosomes with Htz1/H2B dimers. We use cryoelectron microscopy to determine the structure of an enzyme-bound hexasome intermediate in the reaction pathway of histone exchange, in which an H2A/H2B dimer has been extracted from a nucleosome prior to the insertion of a dimer comprising Htz1/H2B. The structure reveals a key role for the Swc5 subunit in stabilizing the unwrapping of DNA from the histone core of the hexasome. By engineering a crosslink between an Htz1/H2B dimer and its chaperone protein Chz1, we show that this blocks histone exchange by SWR1 but allows the incoming chaperone-dimer complex to insert into the hexasome. We use this reagent to trap an SWR1/hexasome complex with an incoming Htz1/H2B dimer that shows how the reaction progresses to the next step. Taken together the structures reveal insights into the mechanism of histone exchange by SWR1 complex.
    Keywords:  SWR1 complex; chromatin remodeling; histone exchange
    DOI:  https://doi.org/10.1016/j.molcel.2024.08.015
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