bims-crepig Biomed News
on Chromatin regulation and epigenetics in cell fate and cancer
Issue of 2024‒10‒06
fifteen papers selected by
Connor Rogerson, University of Cambridge
  1. Developmental and housekeeping transcriptional programs display distinct modes of enhancer-enhancer cooperativity in Drosophila.
  2. Context transcription factors establish cooperative environments and mediate enhancer communication.
  3. Mesoscale chromatin confinement facilitates target search of pioneer transcription factors in live cells.
  4. ZIC2 and ZIC3 promote SWI/SNF recruitment to safeguard progression towards human primed pluripotency.
  5. Molecular basis of global promoter sensing and nucleosome capture by the SWR1 chromatin remodeler.
  6. Nr5a2 is dispensable for zygotic genome activation but essential for morula development.
  7. A suboptimal OCT4-SOX2 binding site facilitates the naïve-state specific function of a Klf4 enhancer.
  8. An RNA-centric view of transcription and genome organization.
  9. RNA m5C oxidation by TET2 regulates chromatin state and leukaemogenesis.
  10. Transcription factor condensates, 3D clustering, and gene expression enhancement of the MET regulon.
  11. Transcription factor PATZ1 promotes adipogenesis by controlling promoter regulatory loci of adipogenic factors.
  12. RNA polymerase II transcription initiation in holo-TFIID-depleted mouse embryonic stem cells.
  13. Enhancer landscape of lung neuroendocrine tumors reveals regulatory and developmental signatures with potential theranostic implications.
  14. Relocalizing transcriptional kinases to activate apoptosis.
  15. Identifying the "stripe" transcription factors and cooperative binding related to DNA methylation.
  1. Nat Commun. 2024 Oct 03. 15(1): 8584
    Developmental and housekeeping transcriptional programs display distinct modes of enhancer-enhancer cooperativity in Drosophila.
    Vincent Loubiere, Bernardo P de Almeida, Michaela Pagani, Alexander Stark.
      Genomic enhancers are key transcriptional regulators which, upon the binding of sequence-specific transcription factors, activate their cognate target promoters. Although enhancers have been extensively studied in isolation, a substantial number of genes have more than one simultaneously active enhancer, and it remains unclear how these cooperate to regulate transcription. Using Drosophila melanogaster S2 cells as a model, we assay the activities of more than a thousand individual enhancers and about a million enhancer pairs toward housekeeping and developmental core promoters with STARR-seq. We report that housekeeping and developmental enhancers show distinct modes of enhancer-enhancer cooperativity: while housekeeping enhancers are additive such that their combined activity mirrors the sum of their individual activities, developmental enhancers are super-additive and combine multiplicatively. Super-additivity between developmental enhancers is promiscuous and neither depends on the enhancers' endogenous genomic contexts nor on specific transcription factor motif signatures. However, it can be further boosted by Twist and Trl motifs and saturates for the highest levels of enhancer activity. These results have important implications for our understanding of gene regulation in complex multi-enhancer developmental loci and genomically clustered housekeeping genes, providing a rationale to interpret the transcriptional impact of non-coding mutations at different loci.
    DOI:  https://doi.org/10.1038/s41467-024-52921-2
  2. Nat Genet. 2024 Oct 03.
    Context transcription factors establish cooperative environments and mediate enhancer communication.
    Judith F Kribelbauer-Swietek, Olga Pushkarev, Vincent Gardeux, Katerina Faltejskova, Julie Russeil, Guido van Mierlo, Bart Deplancke.
      Many enhancers control gene expression by assembling regulatory factor clusters, also referred to as condensates. This process is vital for facilitating enhancer communication and establishing cellular identity. However, how DNA sequence and transcription factor (TF) binding instruct the formation of high regulatory factor environments remains poorly understood. Here we developed a new approach leveraging enhancer-centric chromatin accessibility quantitative trait loci (caQTLs) to nominate regulatory factor clusters genome-wide. By analyzing TF-binding signatures within the context of caQTLs and comparing episomal versus endogenous enhancer activities, we discovered a class of regulators, 'context-only' TFs, that amplify the activity of cell type-specific caQTL-binding TFs, that is, 'context-initiator' TFs. Similar to super-enhancers, enhancers enriched for context-only TF-binding sites display high coactivator binding and sensitivity to bromodomain-inhibiting molecules. We further show that binding sites for context-only and context-initiator TFs underlie enhancer coordination, providing a mechanistic rationale for how a loose TF syntax confers regulatory specificity.
    DOI:  https://doi.org/10.1038/s41588-024-01892-7
  3. Nat Struct Mol Biol. 2024 Oct 04.
    Mesoscale chromatin confinement facilitates target search of pioneer transcription factors in live cells.
    Zuhui Wang, Bo Wang, Di Niu, Chao Yin, Ying Bi, Claudia Cattoglio, Kyle M Loh, Luke D Lavis, Hao Ge, Wulan Deng.
      Pioneer transcription factors (PTFs) possess the unique capability to access closed chromatin regions and initiate cell fate changes, yet the underlying mechanisms remain elusive. Here, we characterized the single-molecule dynamics of PTFs targeting chromatin in living cells, revealing a notable 'confined target search' mechanism. PTFs such as FOXA1, FOXA2, SOX2, OCT4 and KLF4 sampled chromatin more frequently than non-PTF MYC, alternating between fast free diffusion in the nucleus and slower confined diffusion within mesoscale zones. Super-resolved microscopy showed closed chromatin organized as mesoscale nucleosome-dense domains, confining FOXA2 diffusion locally and enriching its binding. We pinpointed specific histone-interacting disordered regions, distinct from DNA-binding domains, crucial for confined target search kinetics and pioneer activity within closed chromatin. Fusion to other factors enhanced pioneer activity. Kinetic simulations suggested that transient confinement could increase target association rate by shortening search time and binding repeatedly. Our findings illuminate how PTFs recognize and exploit closed chromatin organization to access targets, revealing a pivotal aspect of gene regulation.
    DOI:  https://doi.org/10.1038/s41594-024-01385-5
  4. Nat Commun. 2024 Oct 02. 15(1): 8539
    ZIC2 and ZIC3 promote SWI/SNF recruitment to safeguard progression towards human primed pluripotency.
    Ishtiaque Hossain, Pierre Priam, Sofia C Reynoso, Sahil Sahni, Xiao X Zhang, Laurence Côté, Joelle Doumat, Candus Chik, Tianxin Fu, Julie A Lessard, William A Pastor.
      The primed epiblast acts as a transitional stage between the relatively homogeneous naïve epiblast and the gastrulating embryo. Its formation entails coordinated changes in regulatory circuits driven by transcription factors and epigenetic modifications. Using a multi-omic approach in human embryonic stem cell models across the spectrum of peri-implantation development, we demonstrate that the transcription factors ZIC2 and ZIC3 have overlapping but essential roles in opening primed-specific enhancers. Together, they are essential to facilitate progression to and maintain primed pluripotency. ZIC2/3 accomplish this by recruiting SWI/SNF to chromatin and loss of ZIC2/3 or degradation of SWI/SNF both prevent enhancer activation. Loss of ZIC2/3 also results in transcriptome changes consistent with perturbed Polycomb activity and a shift towards the expression of genes linked to differentiation towards the mesendoderm. Additionally, we find an intriguing dependency on the transcriptional machinery for sustained recruitment of ZIC2/3 over a subset of primed-hESC specific enhancers. Taken together, ZIC2 and ZIC3 regulate highly dynamic lineage-specific enhancers and collectively act as key regulators of human primed pluripotency.
    DOI:  https://doi.org/10.1038/s41467-024-52431-1
  5. Cell. 2024 Sep 27. pii: S0092-8674(24)01025-0. [Epub ahead of print]
    Molecular basis of global promoter sensing and nucleosome capture by the SWR1 chromatin remodeler.
    Robert K Louder, Giho Park, Ziyang Ye, Justin S Cha, Anne M Gardner, Qin Lei, Anand Ranjan, Eva Höllmüller, Florian Stengel, B Franklin Pugh, Carl Wu.
      The SWR1 chromatin remodeling complex is recruited to +1 nucleosomes downstream of transcription start sites of eukaryotic promoters, where it exchanges histone H2A for the specialized variant H2A.Z. Here, we use cryoelectron microscopy (cryo-EM) to resolve the structural basis of the SWR1 interaction with free DNA, revealing a distinct open conformation of the Swr1 ATPase that enables sliding from accessible DNA to nucleosomes. A complete structural model of the SWR1-nucleosome complex illustrates critical roles for Swc2 and Swc3 subunits in oriented nucleosome engagement by SWR1. Moreover, an extended DNA-binding α helix within the Swc3 subunit enables sensing of nucleosome linker length and is essential for SWR1-promoter-specific recruitment and activity. The previously unresolved N-SWR1 subcomplex forms a flexible extended structure, enabling multivalent recognition of acetylated histone tails by reader domains to further direct SWR1 toward the +1 nucleosome. Altogether, our findings provide a generalizable mechanism for promoter-specific targeting of chromatin and transcription complexes.
    Keywords:  +1 nucleosome; DNA sliding; H2A.Z; SWR1; chromatin remodeler; cryo-EM; histone acetylation; histone exchange; histone reader; promoter
    DOI:  https://doi.org/10.1016/j.cell.2024.09.007
  6. Science. 2024 Oct 04. 386(6717): eadg7325
    Nr5a2 is dispensable for zygotic genome activation but essential for morula development.
    Nicola Festuccia, Sandrine Vandormael-Pournin, Almira Chervova, Anna Geiselman, Francina Langa-Vives, Rémi-Xavier Coux, Inma Gonzalez, Guillaume Giraud Collet, Michel Cohen-Tannoudji, Pablo Navarro.
      Early embryogenesis is driven by transcription factors (TFs) that first activate the zygotic genome and then specify the lineages constituting the blastocyst. Although the TFs specifying the blastocyst's lineages are well characterized, those playing earlier roles remain poorly defined. Using mouse models of the TF Nr5a2, we show that Nr5a2-/- embryos arrest at the early morula stage and exhibit altered lineage specification, frequent mitotic failure, and substantial chromosome segregation defects. Although NR5A2 plays a minor but measurable role during zygotic genome activation, it predominantly acts as a master regulator at the eight-cell stage, controlling expression of lineage-specifying TFs and genes involved in mitosis, telomere maintenance, and DNA repair. We conclude that NR5A2 coordinates proliferation, genome stability, and lineage specification to ensure correct morula development.
    DOI:  https://doi.org/10.1126/science.adg7325
  7. PLoS One. 2024 ;19(9): e0311120
    A suboptimal OCT4-SOX2 binding site facilitates the naïve-state specific function of a Klf4 enhancer.
    Jack B Waite, RuthMabel Boytz, Alexis R Traeger, Torrey M Lind, Koya Lumbao-Conradson, Sharon E Torigoe.
      Enhancers have critical functions in the precise, spatiotemporal control of transcription during development. It is thought that enhancer grammar, or the characteristics and arrangements of transcription factor binding sites, underlie the specific functions of developmental enhancers. In this study, we sought to identify grammatical constraints that direct enhancer activity in the naïve state of pluripotency, focusing on the enhancers for the naïve-state specific gene, Klf4. Using a combination of biochemical tests, reporter assays, and endogenous mutations in mouse embryonic stem cells, we have studied the binding sites for the transcription factors OCT4 and SOX2. We have found that the three Klf4 enhancers contain suboptimal OCT4-SOX2 composite binding sites. Substitution with a high-affinity OCT4-SOX2 binding site in Klf4 enhancer E2 rescued enhancer function and Klf4 expression upon loss of the ESRRB and STAT3 binding sites. We also observed that the low-affinity of the OCT4-SOX2 binding site is crucial to drive the naïve-state specific activities of Klf4 enhancer E2. Altogether, our work suggests that the affinity of OCT4-SOX2 binding sites could facilitate enhancer functions in specific states of pluripotency.
    DOI:  https://doi.org/10.1371/journal.pone.0311120
  8. Mol Cell. 2024 Oct 03. pii: S1097-2765(24)00698-1. [Epub ahead of print]84(19): 3627-3643
    An RNA-centric view of transcription and genome organization.
    Jonathan E Henninger, Richard A Young.
      Foundational models of transcriptional regulation involve the assembly of protein complexes at DNA elements associated with specific genes. These assemblies, which can include transcription factors, cofactors, RNA polymerase, and various chromatin regulators, form dynamic spatial compartments that contribute to both gene regulation and local genome architecture. This DNA-protein-centric view has been modified with recent evidence that RNA molecules have important roles to play in gene regulation and genome structure. Here, we discuss evidence that gene regulation by RNA occurs at multiple levels that include assembly of transcriptional complexes and genome compartments, feedback regulation of active genes, silencing of genes, and control of protein kinases. We thus provide an RNA-centric view of transcriptional regulation that must reside alongside the more traditional DNA-protein-centric perspectives on gene regulation and genome architecture.
    Keywords:  RNA; RNA-binding proteins; biomolecular condensates; feedback; gene expression; genome organization; transcription; transcription factors
    DOI:  https://doi.org/10.1016/j.molcel.2024.08.021
  9. Nature. 2024 Oct 02.
    RNA m5C oxidation by TET2 regulates chromatin state and leukaemogenesis.
    Zhongyu Zou, Xiaoyang Dou, Ying Li, Zijie Zhang, Juan Wang, Boyang Gao, Yu Xiao, Yiding Wang, Lijie Zhao, Chenxi Sun, Qinzhe Liu, Xianbin Yu, Hao Wang, Juyeong Hong, Qing Dai, Feng-Chun Yang, Mingjiang Xu, Chuan He.
      Mutation of tet methylcytosine dioxygenase 2 (encoded by TET2) drives myeloid malignancy initiation and progression1-3. TET2 deficiency is known to cause a globally opened chromatin state and activation of genes contributing to aberrant haematopoietic stem cell self-renewal4,5. However, the open chromatin observed in TET2-deficient mouse embryonic stem cells, leukaemic cells and haematopoietic stem and progenitor cells5 is inconsistent with the designated role of DNA 5-methylcytosine oxidation of TET2. Here we show that chromatin-associated retrotransposon RNA 5-methylcytosine (m5C) can be recognized by the methyl-CpG-binding-domain protein MBD6, which guides deubiquitination of nearby monoubiquitinated Lys119 of histone H2A (H2AK119ub) to promote an open chromatin state. TET2 oxidizes m5C and antagonizes this MBD6-dependent H2AK119ub deubiquitination. TET2 depletion thereby leads to globally decreased H2AK119ub, more open chromatin and increased transcription in stem cells. TET2-mutant human leukaemia becomes dependent on this gene activation pathway, with MBD6 depletion selectively blocking proliferation of TET2-mutant leukaemic cells and largely reversing the haematopoiesis defects caused by Tet2 loss in mouse models. Together, our findings reveal a chromatin regulation pathway by TET2 through retrotransposon RNA m5C oxidation and identify the downstream MBD6 protein as a feasible target for developing therapies specific against TET2 mutant malignancies.
    DOI:  https://doi.org/10.1038/s41586-024-07969-x
  10. Elife. 2024 Sep 30. pii: RP96028. [Epub ahead of print]13
    Transcription factor condensates, 3D clustering, and gene expression enhancement of the MET regulon.
    James Lee, Leman Simpson, Yi Li, Samuel Becker, Fan Zou, Xin Zhang, Lu Bai.
      Some transcription factors (TFs) can form liquid-liquid phase separated (LLPS) condensates. However, the functions of these TF condensates in 3-Dimentional (3D) genome organization and gene regulation remain elusive. In response to methionine (met) starvation, budding yeast TF Met4 and a few co-activators, including Met32, induce a set of genes involved in met biosynthesis. Here, we show that the endogenous Met4 and Met32 form co-localized puncta-like structures in yeast nuclei upon met depletion. Recombinant Met4 and Met32 form mixed droplets with LLPS properties in vitro. In relation to chromatin, Met4 puncta co-localize with target genes, and at least a subset of these target genes is clustered in 3D in a Met4-dependent manner. A MET3pr-GFP reporter inserted near several native Met4-binding sites becomes co-localized with Met4 puncta and displays enhanced transcriptional activity. A Met4 variant with a partial truncation of an intrinsically disordered region (IDR) shows less puncta formation, and this mutant selectively reduces the reporter activity near Met4-binding sites to the basal level. Overall, these results support a model where Met4 and co-activators form condensates to bring multiple target genes into a vicinity with higher local TF concentrations, which facilitates a strong response to methionine depletion.
    Keywords:  3D genome; S. cerevisiae; biological condensates; chromosomes; gene clustering; gene expression; gene regulation; phase separation; transcription factors
    DOI:  https://doi.org/10.7554/eLife.96028
  11. Nat Commun. 2024 Oct 02. 15(1): 8533
    Transcription factor PATZ1 promotes adipogenesis by controlling promoter regulatory loci of adipogenic factors.
    Sanil Patel, Khatanzul Ganbold, Chung Hwan Cho, Juwairriyyah Siddiqui, Ramazan Yildiz, Njeri Sparman, Shani Sadeh, Christy M Nguyen, Jiexin Wang, Julian P Whitelegge, Susan K Fried, Hironori Waki, Claudio J Villanueva, Marcus M Seldin, Shinya Sakaguchi, Wilfried Ellmeier, Peter Tontonoz, Prashant Rajbhandari.
      White adipose tissue (WAT) is essential for lipid storage and systemic energy homeostasis. Understanding adipocyte formation and stability is key to developing therapies for obesity and metabolic disorders. Through a high-throughput cDNA screen, we identified PATZ1, a POZ/BTB and AT-Hook Containing Zinc Finger 1 protein, as an important adipogenic transcription factor. PATZ1 is expressed in human and mouse adipocyte precursor cells (APCs) and adipocytes. In cellular models, PATZ1 promotes adipogenesis via protein-protein interactions and DNA binding. PATZ1 ablation in mouse adipocytes and APCs leads to a reduced APC pool, decreased fat mass, and hypertrophied adipocytes. ChIP-Seq and RNA-seq analyses show that PATZ1 supports adipogenesis by interacting with transcriptional machinery at the promoter regions of key early adipogenic factors. Mass-spec results show that PATZ1 associates with GTF2I, with GTF2I modulating PATZ1's function during differentiation. These findings underscore PATZ1's regulatory role in adipocyte differentiation and adiposity, offering insights into adipose tissue development.
    DOI:  https://doi.org/10.1038/s41467-024-52917-y
  12. Cell Rep. 2024 Sep 30. pii: S2211-1247(24)01142-2. [Epub ahead of print]43(10): 114791
    RNA polymerase II transcription initiation in holo-TFIID-depleted mouse embryonic stem cells.
    Vincent Hisler, Paul Bardot, Dylane Detilleux, Andrea Bernardini, Matthieu Stierle, Emmanuel Garcia Sanchez, Claire Richard, Lynda Hadj Arab, Cynthia Ehrhard, Bastien Morlet, Yavor Hadzhiev, Matthieu Jung, Stéphanie Le Gras, Luc Négroni, Ferenc Müller, László Tora, Stéphane D Vincent.
      The recognition of core promoter sequences by TFIID is the first step in RNA polymerase II (Pol II) transcription initiation. Metazoan holo-TFIID is a trilobular complex, composed of the TATA binding protein (TBP) and 13 TBP-associated factors (TAFs). Why and how TAFs are necessary for the formation of TFIID domains and how they contribute to transcription initiation remain unclear. Inducible TAF7 or TAF10 depletion, followed by comprehensive analysis of TFIID subcomplex formation, chromatin binding, and nascent transcription in mouse embryonic stem cells, result in the formation of a TAF7-lacking TFIID or a minimal core-TFIID complex, respectively. These partial complexes support TBP recruitment at promoters and nascent Pol II transcription at most genes early after depletion, but importantly, TAF10 is necessary for efficient Pol II pausing. We show that partially assembled TFIID complexes can sustain Pol II transcription initiation but cannot replace holo-TFIID over several cell divisions and/or development.
    Keywords:  CP: Molecular biology; RNA polymerase II; TAF10; TAF7; TATA binding protein; TBP; TBP-associated factor; TFIID; complex assembly; mouse embryonic stem cells; nascent transcription
    DOI:  https://doi.org/10.1016/j.celrep.2024.114791
  13. Proc Natl Acad Sci U S A. 2024 Oct 08. 121(41): e2405001121
    Enhancer landscape of lung neuroendocrine tumors reveals regulatory and developmental signatures with potential theranostic implications.
    Ester Davis, Shani Avniel-Polak, Shahd Abu-Kamel, Israel Antman, Tsipora Saadoun, Chava Brim, Mohammad Jumaa, Yariv Maron, Ofra Maimon, Anat Bel-Ange, Karine Atlan, Tomer Tzur, Firas Abu Akar, Ori Wald, Uzi Izhar, Merav Hecht, Simona Grozinsky-Glasberg, Yotam Drier.
      Well-differentiated low-grade lung neuroendocrine tumors (lung carcinoids or LNETs) are histopathologically classified as typical and atypical LNETs, but each subtype is still heterogeneous at both the molecular level and its clinical manifestation. Here, we report genome-wide profiles of primary LNETs' cis-regulatory elements by H3K27ac ChIP-seq with matching RNA-seq profiles. Analysis of these regulatory landscapes revealed three regulatory subtypes, independent of the typical/atypical classification. We identified unique differentiation signals that delineate each subtype. The "proneuronal" subtype emerges under the influence of ASCL1, SOX4, and TCF4 transcription factors, embodying a pronounced proneuronal signature. The "luminal-like" subtype is characterized by gain of acetylation at markers of luminal cells and GATA2 activation and loss of LRP5 and OTP. The "HNF+" subtype is characterized by a robust enhancer landscape driven by HNF1A, HNF4A, and FOXA3, with notable acetylation and expression of FGF signaling genes, especially FGFR3 and FGFR4, pivotal components of the FGF pathway. Our findings not only deepen the understanding of LNETs' regulatory and developmental diversity but also spotlight the HNF+ subtype's reliance on FGFR signaling. We demonstrate that targeting this pathway with FGF inhibitors curtails tumor growth both in vitro and in xenograft models, unveiling a potential vulnerability and paving the way for targeted therapies. Overall, our work provides an important resource for studying LNETs to reveal regulatory networks, differentiation signals, and therapeutically relevant dependencies.
    Keywords:  FGFR signaling; enhancers; epigenomics; neuroendocrine tumors; pulmonary carcinoids
    DOI:  https://doi.org/10.1073/pnas.2405001121
  14. Science. 2024 Oct 04. 386(6717): eadl5361
    Relocalizing transcriptional kinases to activate apoptosis.
    Roman C Sarott, Sai Gourisankar, Basel Karim, Sabin Nettles, Haopeng Yang, Brendan G Dwyer, Juste M Simanauskaite, Jason Tse, Hind Abuzaid, Andrey Krokhotin, Tinghu Zhang, Stephen M Hinshaw, Michael R Green, Gerald R Crabtree, Nathanael S Gray.
      Kinases are critical regulators of cellular function that are commonly implicated in the mechanisms underlying disease. Most drugs that target kinases are molecules that inhibit their catalytic activity, but here we used chemically induced proximity to convert kinase inhibitors into activators of therapeutic genes. We synthesized bivalent molecules that link ligands of the transcription factor B cell lymphoma 6 (BCL6) to inhibitors of cyclin-dependent kinases (CDKs). These molecules relocalized CDK9 to BCL6-bound DNA and directed phosphorylation of RNA polymerase II. The resulting expression of pro-apoptotic, BCL6-target genes caused killing of diffuse large B cell lymphoma cells and specific ablation of the BCL6-regulated germinal center response. Genomics and proteomics corroborated a gain-of-function mechanism in which global kinase activity was not inhibited but rather redirected. Thus, kinase inhibitors can be used to context-specifically activate transcription.
    DOI:  https://doi.org/10.1126/science.adl5361
  15. Commun Biol. 2024 Oct 05. 7(1): 1265
    Identifying the "stripe" transcription factors and cooperative binding related to DNA methylation.
    Ximei Luo, Quan Zou.
      DNA methylation plays a critical role in gene regulation by modulating the DNA binding of transcription factors (TFs). This study integrates TFs' ChIP-seq profiles with WGBS profiles to investigate how DNA methylation affects protein interactions. Statistical methods and a 5-letter DNA motif calling model have been developed to characterize DNA sequences bound by proteins, while considering the effects of DNA modifications. By employing these methods, 79 significant universal "stripe" TFs and cofactors (USFs), 2360 co-binding protein pairs, and distinct protein modules associated with various DNA methylation states have been identified. The USFs hint a regulatory hierarchy within these protein interactions. Proteins preferentially bind to non-CpG sites in methylated regions, indicating binding affinity is not solely CpG-dependent. Proteins involved in methylation-specific USFs and cobinding pairs play essential roles in promoting and sustaining DNA methylation through interacting with DNMTs or inhibiting TET binding. These findings underscore the interplay between protein binding and methylation, offering insights into epigenetic regulation in cellular biology.
    DOI:  https://doi.org/10.1038/s42003-024-06992-y
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