H3K27me3-rich genomic regions can function as silencers to repress gene expression via chromatin interactions
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Abstract
The mechanisms underlying gene repression and silencers are poorly understood. Here we investigate the hypothesis that H3K27me3-rich regions of the genome, defined from clusters of H3K27me3 peaks, may be used to identify silencers that can regulate gene expression via proximity or looping. We find that H3K27me3-rich regions are associated with chromatin interactions and interact preferentially with each other. H3K27me3-rich regions component removal at interaction anchors by CRISPR leads to upregulation of interacting target genes, altered H3K27me3 and H3K27ac levels at interacting regions, and altered chromatin interactions. Chromatin interactions did not change at regions with high H3K27me3, but regions with low H3K27me3 and high H3K27ac levels showed changes in chromatin interactions. Cells with H3K27me3-rich regions knockout also show changes in phenotype associated with cell identity, and altered xenograft tumor growth. Finally, we observe that H3K27me3-rich regions-associated genes and long-range chromatin interactions are susceptible to H3K27me3 depletion. Our results characterize H3K27me3-rich regions and their mechanisms of functioning via looping.
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EZH2 binding sites mostly overlapped with H3K27me3 peaks in P-S loop anchors.
“Next, we performed CUT&Tag for EZH2, a subunit of Polycomb repressive complex II, in THP-1 cells and observed that EZH2 binding sites mostly overlapped with H3K27me3 peaks in the P-S loop anchors (Extended Data Fig. 6d), consistent with the previously reported promoter-silencer loops30,31.”
From Subtype-specific 3D genome alteration in acute myeloid leukaemia (2022) · cites this paper as [31]
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The molecular principles of gene regulation by Polycomb repressive complexes
Blackledge, N. P., & Klose, R. J. (2021) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-021-00398-y · Cited by 470 · see citing works
A cis-regulatory atlas in maize at single-cell resolution
Marand, A. P., Chen, Z., Gallavotti, A., & Schmitz, R. J. (2021) · Cell · doi:10.1016/j.cell.2021.04.014 · Cited by 379 · see citing works
cis-Regulatory Elements in Plant Development, Adaptation, and Evolution
Marand, A. P., Eveland, A. L., Kaufmann, K., & Springer, N. M. (2023) · Annual Review of Plant Biology · doi:10.1146/annurev-arplant-070122-030236 · Cited by 342 · see citing works
Deciphering the multi-scale, quantitative cis-regulatory code
Kim, S., & Wysocka, J. (2023) · Molecular Cell · doi:10.1016/j.molcel.2022.12.032 · Cited by 282 · see citing works
Subtype-specific 3D genome alteration in acute myeloid leukaemia
Xu, J., Song, F., Lyu, H., Kobayashi, M., Zhang, B., Zhao, Z., Hou, Y., Wang, X., Luan, Y., Jia, B., et al. (2022) · Nature · doi:10.1038/s41586-022-05365-x · Cited by 208 · see citing works
Mechanisms of Polycomb group protein function in cancer
Parreno, V., Martinez, A., & Cavalli, G. (2022) · Cell Research · doi:10.1038/s41422-021-00606-6 · Cited by 147 · see citing works
“Interestingly, co-repression of several tumor suppressors was suggested to participate in tumor growth.(105,106) An established tumor state can also participate a posteriori in the redistribution of EZH2 on ectopic targets, triggering changes in cell identity due to misexpression of homeotic genes.”
BackgroundMechanisms of action and resistance in histone methylation-targeted therapy
Yamagishi, M., Kuze, Y., Kobayashi, S., Nakashima, M., Morishima, S., Kawamata, T., Makiyama, J., Suzuki, K., Seki, M., Abe, K., et al. (2024) · Nature · doi:10.1038/s41586-024-07103-x · Cited by 115 · see citing works
Identification of non-coding silencer elements and their regulation of gene expression
Pang, B., van Weerd, J. H., Hamoen, F. L., & Snyder, M. P. (2022) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-022-00549-9 · Cited by 97 · see citing works
“Epigenomic and other characteristics As mentioned earlier, specific epigenetic modifications are associated with distinct NCREs, and some silencers are enriched in H3K27me3 (refs.(56,64,84,85)).”
BackgroundHiCAR is a robust and sensitive method to analyze open-chromatin-associated genome organization
Wei, X., Yu, X., Peters, D., Marius, C., Sun, T., Shan, R., Ou, J., Lin, X., Yue, F., Li, W., et al. (2022) · Molecular Cell · doi:10.1016/j.molcel.2022.01.023 · Cited by 83 · see citing works
Epigenetic regulation of B cells and its role in autoimmune pathogenesis
Xiao, F., Rui, K., Shi, X., Wu, H., Cai, X., Lui, K. O., Lu, Q., Ballestar, E., Tian, J., Zou, H., et al. (2022) · Cellular and Molecular Immunology · doi:10.1038/s41423-022-00933-7 · Cited by 78 · see citing works
“However, trimethylation at Lys9 and Lys27 of histone H3 (H3K9me3 and H3K27me3, respectively) can function as a silencer to repress gene expression by modifying chromatin architecture and interactions [20, 21].”
BackgroundEndogenous Retroviruses as Modulators of Innate Immunity
Russ, E. U., & Iordanskiy, S. (2023) · Pathogens · doi:10.3390/pathogens12020162 · Cited by 70 · see citing works
Chromatin Conformation in Development and Disease
Boltsis, I., Grosveld, F. G., Giraud, G., & Kolovos, P. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.723859 · Cited by 56 · see citing works
Enhancer–silencer transitions in the human genomePreprint
Huang, D., & Ovcharenko, I. (2022) · Genome Research · doi:10.1101/gr.275992.121 · Cited by 57 · see citing works
“H3K27me3 modification has been evidenced to take part in both repressive mechanisms (Ogiyama et al. 2018; Cai et al. 2021).”
BackgroundCell tumbling enhances stem cell differentiation in hydrogels via nuclear mechanotransduction
Ayushman, M., Mikos, G., Tong, X., Sinha, S., López-Fuentes, E., Jones, S., Cai, P. C., Lee, H. P., Morrison, A. J., Spakowitz, A. J., et al. (2024) · Nature Materials · doi:10.1038/s41563-024-02038-0 · Cited by 54 · see citing works
“Therefore, we also characterized H3K27me3, a histone modification associated with active transcription repression and heterochromatin linked to differentiation-specific genes 31,32 .”
Epiphany: predicting Hi-C contact maps from 1D epigenomic signals
Yang, R., Das, A., Gao, V. R., Karbalayghareh, A., Noble, W. S., Bilmes, J. A., & Leslie, C. (2021) · bioRxiv · doi:10.1186/s13059-023-02934-9 · Cited by 64 · see citing works
“We next found another example of a cell-type-specific region around the gene CPED1 [24], and we tested whether Epiphany could predict the difference.”
BackgroundSuper-Enhancers, Phase-Separated Condensates, and 3D Genome Organization in Cancer
Tang, S., Vijayakumar, U., Zhang, Y., & Fullwood, M. (2022) · Cancers · doi:10.3390/cancers14122866 · Cited by 46 · see citing works
Self-citationRole of primary aging hallmarks in Alzheimer´s disease
Zhao, J., & Huai, J. (2022) · Theranostics · doi:10.7150/thno.79535 · Cited by 53 · see citing works
“Of note, H3K9ac has been shown to co-localize with H3K14ac on the previously described poised promoters harbouring H3K4me3 and H3K27me3 [209, 251, 252].”
BackgroundInfluentialTopography of mutational signatures in human cancer
Otlu, B., Díaz‐Gay, M., Vermes, I., Bergstrom, E. N., Zhivagui, M., Barnes, M. D., & Alexandrov, L. B. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112930 · Cited by 47 · see citing works
An expanded registry of candidate cis-regulatory elements
Moore, J. E., Pratt, H., Fan, K., Phalke, N. N., Fisher, J., Elhajjajy, S. I., Andrews, G., Gao, M., Shedd, N., Fu, Y., et al. (2026) · Nature · doi:10.1038/s41586-025-09909-9 · Cited by 90 · see citing works
Epigenetic reprogramming during the maternal‐to‐zygotic transition
Chen, Y., Wang, L., Guo, F., Dai, X., & Zhang, X. (2023) · MedComm · doi:10.1002/mco2.331 · Cited by 47 · see citing works
Low RNA stability signifies increased post-transcriptional regulation of cell identity genes
Li, Y., Yang, Y., Lv, J., Gao, X., Yu, Y., Babu, S. S., Bruno, I., Zhao, D., Xia, B., Peng, W., et al. (2023) · Nucleic Acids Research · doi:10.1093/nar/gkad300 · Cited by 43 · see citing works
PRC2, Chromatin Regulation, and Human Disease: Insights From Molecular Structure and Function
Liu, X., & Liu, X. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.894585 · Cited by 44 · see citing works
“dependent long-range chromatin interactions (124, 125).”
Wnuk, A., Przepiórska, K., Pietrzak, B. A., & Kajta, M. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24044043 · Cited by 43 · see citing works
“The role of PRC2 in silencing gene expression consists of adding methyl groups at Lys27 of histone H3 to form H3K27me3, a commonly known marker of gene repression [46,47].”
BackgroundGlucose Deprivation Promotes Pseudohypoxia and Dedifferentiation in Lung Adenocarcinoma
Saggese, P., Pandey, A., Alcaraz, M., Fung, E., Hall, A., Yanagawa, J., Rodriguez, E. F., Grogan, T., Giurato, G., Nassa, G., et al. (2023) · Cancer Research · doi:10.1158/0008-5472.can-23-1148 · Cited by 44 · see citing works
Thrombocytopenia Independently Leads to Changes in Monocyte Immune Function
Li, C., Ture, S. K., Nieves-López, B., Blick-Nitko, S. K., Maurya, P., Livada, A. C., Stahl, T. J., Kim, M., Pietropaoli, A. P., & Morrell, C. N. (2024) · Circulation Research · doi:10.1161/circresaha.123.323662 · Cited by 44 · see citing works
“43,44 Circulating monocytes isolated from thrombocytopenic and CD47 −/− mice had less H3K9me3 and H3K27me3 compared with WT mouse monocytes (Figure 6B), and monocytes H3K9me3 and H3K27me3 were increased more by WT platelets than CD47 −/− platelets coculture in vitro (Figure 6C).”
Epigenetic Connection of the Calcitonin Gene-Related Peptide and Its Potential in Migraine
Fila, M., Sobczuk, A., Pawłowska, E., & Błasiak, J. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23116151 · Cited by 42 · see citing works
Sánchez-Ceinos, J., Hussain, S., Khan, A. W., Zhang, L., Almahmeed, W. A., Pernow, J., & Cosentino, F. (2024) · Cardiovascular Diabetology · doi:10.1186/s12933-024-02196-0 · Cited by 40 · see citing works
“In particular, trimethylation of lysine 27 on histone 3 (H3K27me3) favours the shift towards heterochromatin, characterized by condensed and silent genomic regions [9].”
BackgroundPolycomb-lamina antagonism partitions heterochromatin at the nuclear periphery
Siegenfeld, A. P., Roseman, S. A., Roh, H., Lue, N. Z., Wagen, C., Zhou, E., Johnstone, S. E., Aryee, M. J., & Liau, B. B. (2022) · Nature Communications · doi:10.1038/s41467-022-31857-5 · Cited by 40 · see citing works
Reduced methylation correlates with diabetic nephropathy risk in type 1 diabetes
Khurana, I., Kaipananickal, H., Maxwell, S., Birkelund, S., Syreeni, A., Forsblom, C. M., Okabe, J., Ziemann, M., Kaspi, A., Rafehi, H., et al. (2023) · Journal of Clinical Investigation · doi:10.1172/jci160959 · Cited by 38 · see citing works
“Indeed, the inability to reactivate FGF18 suggests hyperglycemia may not effectively influence transcription because of differential epigenetic modification of H3K27me3 by EZH2 (72).”
Scaffold, mechanics and functions of nuclear lamins
Buxboim, A., Kronenberg‐Tenga, R., Salajkova, S. A., Avidan, N., Shahak, H., Thurston, A., & Medalia, O. (2023) · FEBS Letters · doi:10.1002/1873-3468.14750 · Cited by 39 · see citing works
“The cell nucleus features a superposition of structural elements spanning a range of dimensional length scales that mechanically translate to a complex viscoelastic load-deformation relationship [85,100,124].”
BackgroundLee, D., Yang, J., & Kim, S. (2022) · Nature Communications · doi:10.1038/s41467-022-34152-5 · Cited by 37 · see citing works
“We conjectured that those pCREs represent transcriptional silencers, since previous studies have shown the potential functionality of distal H3K27me3-rich regions in transcriptional repression 29 .”
BackgroundEpigenetic resetting in the human germ line entails histone modification remodeling
Gruhn, W. H., Tang, W. W. C., Dietmann, S., Alves-Lopes, J. P., Penfold, C. A., Wong, F. C. K., Ramakrishna, N. B., & Surani, M. A. (2023) · Science Advances · doi:10.1126/sciadv.ade1257 · Cited by 38 · see citing works
“Notably, H3K27me3-rich regions in the human genome have recently been shown to loop to proximal or distal promoters mediating gene repression (54).”
BackgroundThe Dynamics of Histone Modifications during Mammalian Zygotic Genome Activation
Lugo, F. S., Barrameda, N. I., Castillo‐Aleman, Y. M., Hernández, I. C., Valverde, C. A. V., Bencomo‐Hernandez, A. A., Ventura‐Carmenate, Y., & Jimenez, R. A. R. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25031459 · Cited by 34 · see citing works
“Furthermore, the divergence continues as H3K27me3-mediated imprinted genes are identified in early mouse embryos, and human orthologs seem to undergo de novo deposition of H3K27me3 in humans [98,111].”
BackgroundAkanbi, C. A., Rotimi, D. E., Ojo, A. B., & Ojo, O. A. (2024) · Toxicology Reports · doi:10.1016/j.toxrep.2024.101885 · Cited by 35 · see citing works
“[34] Repressive marks such as H3K27me3 control gene expression by squelching genes and repetitive DNA segments that may interfere with development [35].”
Rahman, S., Dong, P., Apontes, P., Fernando, M. B., Kosoy, R., Townsley, K., Girdhar, K., Bendl, J., Shao, Z.-P., Misir, R., et al. (2023) · Nucleic Acids Research · doi:10.1093/nar/gkad798 · Cited by 26 · see citing works
Field, N. R., Dickson, K.-A., Nassif, N. T., & Marsh, D. J. (2024) · Cancer Letters · doi:10.1016/j.canlet.2024.217282 · Cited by 33 · see citing works
Top2a promotes the development of social behavior via PRC2 and H3K27me3
Geng, Y., Zhang, T., Alonzo, I. G., Godar, S. C., Yates, C., Pluimer, B. R., Harrison, D. L., Nath, A. K., Yeh, J.-R. J., Drummond, I. A. S., et al. (2022) · Science Advances · doi:10.1126/sciadv.abm7069 · Cited by 29 · see citing works
Comprehensive 3D epigenomic maps define limbal stem/progenitor cell function and identity
Li, M., Huang, H., Wang, B., Jiang, S., Guo, H., Zhu, L., Wu, S., Liu, J., Wang, L., Lan, X., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-28966-6 · Cited by 30 · see citing works
Hijacked enhancer–promoter and silencer–promoter loops in cancer
Wang, X., & Yue, F. (2024) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2024.102199 · Cited by 30 · see citing works
Xie, J., Wu, S., Szadowski, H., Min, S., Yang, Y., Bowman, A. B., Rochet, J., Freeman, J. L., & Yuan, C. (2023) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2023.105023 · Cited by 27 · see citing works
Hybridization and gene expression: Beyond differentially expressed genes
Runemark, A., Moore, E. C., & Larson, E. (2024) · Molecular Ecology · doi:10.1111/mec.17303 · Cited by 26 · see citing works
Non-Coding Variants in Cancer: Mechanistic Insights and Clinical Potential for Personalized Medicine
Lange, M., Begolli, R., & Giakountis, A. (2021) · Non-Coding RNA · doi:10.3390/ncrna7030047 · Cited by 26 · see citing works
Predicting 3D chromatin interactions from DNA sequence using Deep Learning
Piecyk, R. S., Schlegel, L., & Johannes, F. M. (2022) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2022.06.047 · Cited by 25 · see citing works
“In the latter case, enhancer elements could be erroneously brought in physical contacts with proto-oncogenes and thus promote cancer progression [70,71].”
BackgroundXing, C., Zhang, Y., Hu, W., & Zhao, L. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-022-04376-1 · Cited by 26 · see citing works
Self-citationEpigenetic regulation of IPF fibroblast phenotype by glutaminolysis
Xiang, Z., Bai, L., Zhou, J. Q., Cevallos, R. R., Sanders, J. R., Liu, G., Bernard, K. F., & Sanders, Y. Y. (2022) · Molecular Metabolism · doi:10.1016/j.molmet.2022.101655 · Cited by 25 · see citing works
“For specific genes, the increased association of the repressive mark H3K27me3 with gene promoter region represses gene expression [56].”
BackgroundShe, G., Hai, X.-X., Jia, L.-Y., Zhang, Y., Ren, Y., Pang, Z., Wu, L., Han, M.-Z., Zhang, Y., Li, J., et al. (2025) · Redox Biology · doi:10.1016/j.redox.2025.103597 · Cited by 25 · see citing works
“H3K27me3-rich genomic regions often represent transcriptional repression [51], and this was confirmed by our luciferase reporter assay or Western blotting showing transcriptional suppression of Nfs1 .”
Self-citationDeciphering Plant Chromatin Regulation via CRISPR/dCas9-Based Epigenome Engineering
Dubois, A., & Roudier, F. (2021) · Epigenomes · doi:10.3390/epigenomes5030017 · Cited by 23 · see citing works
“These targeted approaches aimed at locally modulating H3K27 methylation could also be useful to assess whether the impact of H3K27-methylated regions can act from a distance, forming loops with transcriptional repression activity [67].”
BackgroundA General Method to Edit Histone H3 Modifications on Chromatin Via Sortase‐Mediated Metathesis
Yang, Q., Gao, Y., Liu, X., Xiao, Y., & Wu, M. (2022) · Angewandte Chemie International Edition · doi:10.1002/anie.202209945 · Cited by 24 · see citing works
Ouyang, W., Zhang, X., Guo, M., Wang, J., Wang, X., Gao, R., Ma, M., Xu, X., Luan, S., Xing, F., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112350 · Cited by 24 · see citing works
Self-citationSon, K. H., Aldonza, M. B. D., Nam, A.-R., Lee, K.-H., Lee, J.-W., Shin, K.-J., Kang, K., & Cho, J. (2023) · Science Advances · doi:10.1126/sciadv.ade3399 · Cited by 27 · see citing works
Epigenetic Effects of Resveratrol on Oncogenic Signaling in Breast Cancer
Kurzava, L., Ma, Y., Yang, T., Lubecka, K., & Stefañska, B. (2024) · Nutrients · doi:10.3390/nu16050699 · Cited by 23 · see citing works
“On the one hand, trimethylation of histone H3 at lysine 27 (H3K27me3) is generally associated with the formation of inaccessible/closed chromatin (heterochromatin) and ultimately gene repression [49].”
BackgroundMun, D., Bhat, F. A., Joshi, N. S., Sandoval, L., Ding, H., Jain, A., Peterson, J. A., Kang, T., Pujari, G. P., Tomlinson, J. L., et al. (2024) · Communications Biology · doi:10.1038/s42003-024-06579-7 · Cited by 23 · see citing works
“…methylation is associated with transcribed regions of active genes 42,43 ; whereas H3K27 methylation is associated silencing gene expression via proximity or looping 44 and H3K79 formylation has been proposed to potentially silence gene expression since it interferes with H3K79 methylation 45 .”
Xue, Y., Liu, L., Zhang, Y., He, Y., Wang, J., Ma, Z.-C., Li, T.-J., Zhang, J.-Y., Huang, Y.-Y., & Gao, Y.-Q. (2024) · Molecular Cancer · doi:10.1186/s12943-024-02100-0 · Cited by 23 · see citing works
“Considering that Polycomb complex could function as silencers via chromatin interactions [40, 41], and that they are associated with DNA methylation alterations in carcinogenesis, we next try to delineate the relationship between H3K27me3 signal, methylation changes, and chromatin structures.”
BackgroundResultSelf-citationExpansion microscopy allows high resolution single cell analysis of epigenetic readers
Acke, A., Belle, S. V., Louis, B., Vitale, R., Rocha, S., Voet, T., Debyser, Z., & Hofkens, J. (2022) · Nucleic Acids Research · doi:10.1093/nar/gkac521 · Cited by 23 · see citing works
“For example, trimethylation of the 27th lysine residue in histone 3 or in short H3K27 can lead to transcriptional suppression (7), whereas H3K36 methylation stimulates gene expression and plays a role in DNA repair and mRNA splicing (8).”
Backgrounddel Blanco, B., Niñerola, S., Martín-González, A. M., Paraíso-Luna, J., Kim, M., Muñoz-Viana, R., Racovac, C., Sanchez-Mut, J., Ruan, Y.-J., & Barco, Á. (2024) · Nature Communications · doi:10.1038/s41467-024-45773-3 · Cited by 17 · see citing works
“The trimethylation of H3K27 is catalyzed by the PRC2 and numerous publications demonstrate that H3K27me3-rich genomic regions function as silencers to repress gene expression via chromatin interactions 30 – 32 .”
Somatic mosaicism in schizophrenia brains reveals prenatal mutational processes
Maury, E. A., Jones, A., Seplyarskiy, V., Nguyen, T. T., Rosenbluh, C., Bae, T., Wang, Y., Abyzov, A., Khoshkhoo, S., Chahine, Y., et al. (2024) · Science · doi:10.1126/science.adq1456 · Cited by 18 · see citing works
“Conversely, we found lower sSNV rate in SCZ at H3K27me3 regions, associated with downregulation of genes and closed chromatin (19) (binomial regression, p = 0.0004, Fig.”
InfluentialInhibition of pancreatic EZH2 restores progenitor insulin in T1D donor
Al‐Hasani, K., Khurana, I., Mariana, L., Loudovaris, T., Maxwell, S., Kaipananickal, H., Okabe, J., Cooper, M. E., & El‐Osta, A. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01034-7 · Cited by 21 · see citing works
“Indeed, H3K27me3 content was shown to influence chromatin domain structures involving looping conformation to regulate Igf2 gene expression.(22) Although other factors involved in regulating insulin expression in T1D pancreata will need to be considered, including incomplete processing of proinsulin,(23) our data emph…”
Balamurli, G., Liew, A. Q. X., Tee, W., & Pervaiz, S. (2024) · Redox Biology · doi:10.1016/j.redox.2024.103441 · Cited by 22 · see citing works
Cornejo‐Páramo, P., Roper, K. E., Degnan, B. M., Degnan, B. M., & Wong, E. S. W. (2022) · Genome Research · doi:10.1101/gr.275864.121 · Cited by 21 · see citing works
Phase Separation: Direct and Indirect Driving Force for High-Order Chromatin Organization
Li, X., An, Z., Zhang, W., & Li, F. (2023) · Genes · doi:10.3390/genes14020499 · Cited by 20 · see citing works
Sun, L., Cao, Y., Li, Z., Liu, Y., Yin, X., Deng, X. W., He, H., & Qian, W. (2023) · Journal of Integrative Plant Biology · doi:10.1111/jipb.13502 · Cited by 20 · see citing works
Targeting KDM2A Enhances T-cell Infiltration in NSD1-Deficient Head and Neck Squamous Cell Carcinoma
Chen, C., Shin, J. H., Fang, Z., Brennan, K., Horowitz, N. B., Pfaff, K. L., Welsh, E. L., Rodig, S. J., Gevaert, O., Gozani, O., et al. (2023) · Cancer Research · doi:10.1158/0008-5472.can-22-3114 · Cited by 20 · see citing works
Epigenetic control of pancreatic cancer metastasis
Krauß, L., Schneider, C., Heßmann, E., Saur, D., & Schneider, G. (2023) · Cancer and Metastasis Reviews · doi:10.1007/s10555-023-10132-z · Cited by 20 · see citing works
“2a) [51].”
Ageing-Related Changes to H3K4me3, H3K27ac, and H3K27me3 in Purified Mouse Neurons
Signal, B., Phipps, A. J., Giles, K. A., Huskins, S. N., Mercer, T. R., Robinson, M. D., Woodhouse, A., & Taberlay, P. C. (2024) · Cells · doi:10.3390/cells13161393 · Cited by 22 · see citing works
Zhu, M., Lu, X., Wang, D., Ma, J., Wang, Y., Wang, R., Wang, H., Cheng, W., & Zhu, Y. (2025) · Epigenomics · doi:10.1080/17501911.2025.2460900 · Cited by 18 · see citing works
Manning, G., Li, A., Eskndir, N., Currey, M. L., & Stephens, A. D. (2025) · Nucleus · doi:10.1080/19491034.2025.2486816 · Cited by 18 · see citing works
“Facultative heterochromatin H3K27me3 has been shown to be important for super silencers driven by chromatin–chromatin looping interactions [75].”
Yuan, J., Jiang, Q., Gong, T., Fan, D., Zhang, J., Chen, F., Zhu, X., Wang, X., Qiao, Y., Chen, H., et al. (2021) · npj Genomic Medicine · doi:10.1038/s41525-021-00232-6 · Cited by 18 · see citing works
Modulation of the high-order chromatin structure by Polycomb complexes
Guo, Y., & Wang, G. G. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.1021658 · Cited by 18 · see citing works
“These findings are in agreement with what was reported in a separate study showing that, in hematological cancer cell lines, the H3K27me3-rich genomic regions interact preferentially with each other, some of which serve as “silencers” for regulating gene expression via chromatin looping (Cai et al., 2021).”
ResultZhu, D., Li, Z., Feng, H., Zheng, J., Xiao, X., Huang, Z., Zheng, L., Guo, J., Ling, F., Li, Y., et al. (2025) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2025-011650 · Cited by 17 · see citing works
Harati, J., Liu, K., Shahsavarani, H., Du, P., Galluzzi, M., Deng, K., Mei, J., Chen, H., Bonakdar, S., Aflatoonian, B., et al. (2022) · ACS Nano · doi:10.1021/acsnano.2c07473 · Cited by 17 · see citing works
Ismail, W. M., Mazzone, A., Ghiraldini, F. G., Kaur, J., Bains, M., Munankarmy, A., Bagwell, M. S., Safgren, S. L., Moore-Weiss, J., Buciuc, M., et al. (2023) · Communications Biology · doi:10.1038/s42003-023-04571-1 · Cited by 17 · see citing works
Toward a comprehensive catalog of regulatory elements
Fan, K., Pfister, E. L., & Weng, Z. (2023) · Human Genetics · doi:10.1007/s00439-023-02519-3 · Cited by 17 · see citing works
“H3K27me3-rich regions can function as silencers (Cai et al. 2021), whereas high levels of H3K9me3 indicate heterochromatin (Becker et al. 2016, 2017; Nicetto and Zaret 2019).”
BackgroundProximity-dependent recruitment of Polycomb repressive complexes by the lncRNA Airn
Braceros, A. K., Schertzer, M. D., Omer, A. D., Trotman, J. B., Davis, E. S., Dowen, J. M., Phanstiel, D. H., Aiden, E. L., & Calabrese, J. M. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112803 · Cited by 17 · see citing works
Attraction and disruption: how loop extrusion and compartmentalisation shape the nuclear genome
Magnitov, M. D., & de Wit, E. (2024) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2024.102194 · Cited by 15 · see citing works
Cis-regulatory elements: systematic identification and horticultural applications
Li, T., Zeng, W., Zhu, F., & Lü, P. (2025) · aBIOTECH · doi:10.1007/s42994-025-00237-0 · Cited by 17 · see citing works
“For example, in animals, active promoters are marked by H3K4me3 and enhancers by H3K9ac and H3K27ac (Heintzman et al. 2007; Shlyueva et al. 2014), while H3K27me3-rich genomic regions can function as silencers (Cai et al. 2021).”
Zhang, Y., See, Y. X., Tergaonkar, V., & Fullwood, M. J. (2022) · Cells · doi:10.3390/cells11091560 · Cited by 15 · see citing works
“[32] were compared to ReSE silencer elements from Pang and Snyder [34] in the K562 cell line; only 10.”
BackgroundMethodInfluentialSelf-citationMouri, K., Dewey, H. B., Castro, R., Berenzy, D., Kales, S., & Tewhey, R. (2022) · Cell Genomics · doi:10.1016/j.xgen.2022.100234 · Cited by 16 · see citing works
“, silencers) and, as a result, a more limited understanding of the scale at which repressor elements function across the genome.(6,7) Thus, an increased focus of repressive elements is critical for understanding the full gene regulatory landscape.”
BackgroundShort tandem repeats are important contributors to silencer elements in T cells
Hussain, S., Sadouni, N., van Essen, D., Dao, L. T. M., Ferré, Q., Charbonnier, G., Torres, M., Gallardo, F., Lecellier, C., Sexton, T., et al. (2023) · Nucleic Acids Research · doi:10.1093/nar/gkad187 · Cited by 16 · see citing works
“Similar approaches identified PRC2-bound silencers playing an important role in mouse development (24) or tumor growth (93).”
BackgroundBisht, S., Mao, Y., & Easwaran, H. (2024) · Current Opinion in Oncology · doi:10.1097/cco.0000000000001020 · Cited by 17 · see citing works
“Changes to heterochromatin during aging and tumorigenesis are associated with large scale three-dimensional genome reorganization and and in cancers [48–53] (Fig.”
BackgroundDisordered regions tune order in chromatin organization and function
Shukla, S., Agarwal, P., & Kumar, A. (2021) · Biophysical Chemistry · doi:10.1016/j.bpc.2021.106716 · Cited by 16 · see citing works
A review of the potential adverse health impacts of atrazine in humans
Arabi, S., Heidari‐Beni, M., Poursafa, P., Roshanaei, M., & Kelishadi, R. (2024) · Reviews on Environmental Health · doi:10.1515/reveh-2024-0094 · Cited by 15 · see citing works
He, Q., Shi, J., Liu, W., Zhao, W. H., Wang, Z., Liu, K., Zhao, D., Wang, S., Guo, Y., Cheng, L., et al. (2022) · Cell Death Discovery · doi:10.1038/s41420-022-01132-z · Cited by 15 · see citing works
“Some previous studies have reported that trimethylation of lysine residue 27 on histone 3 (H3k27me3) inhibits the gene expression whereas removing this methylation mark to promote gene expression via chromatin interactions [19, 20].”
BackgroundZhang, M.-H., Yuan, Y., Liu, L., Wei, Y., Yin, W.-Y., Zheng, L.-Z.-Y., Tang, Y., Lv, Z., & Zhu, F. (2023) · World Journal of Gastroenterology · doi:10.3748/wjg.v29.i31.4706 · Cited by 15 · see citing works
From metabolism to malignancy: the multifaceted role of PGC1α in cancer
Wang, Y., Peng, J., Yang, D., Xing, Z., Jiang, B., Xu, D., Jiang, C., Ouyang, B., & Su, L. (2024) · Frontiers in Oncology · doi:10.3389/fonc.2024.1383809 · Cited by 17 · see citing works
Comorbidity of Novel CRHR2 Gene Variants in Type 2 Diabetes and Depression
Amin, M., Ott, J., Gordon, D., Wu, R., Postolache, T. T., Vergare, M. J., & Gragnoli, C. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23179819 · Cited by 17 · see citing works
“histone modifi tion (H3K27m 3) in neural tissue, causing an epigenet c modification of histone H3 associated with gene down-regulation [35] (Figure 5).”
BackgroundGarofalo, M., Pandini, C., Bordoni, M., Jacchetti, E., Diamanti, L., Carelli, S., Raimondi, M. T., Sproviero, D., Crippa, V., Carra, S., et al. (2022) · Cells · doi:10.3390/cells11020293 · Cited by 14 · see citing works
“Thus, we also evaluated the amount of H3K27me3, an important marker of gene expression repression [25].”
BackgroundMultiomics characteristics and immunotherapeutic potential of EZH2 in pan-cancer
Luo, L., Wang, Z., Hu, T., Feng, Z., Zeng, Q., Shu, X., Wu, A., Huang, P., Cao, Y., Tu, Y., et al. (2022) · Bioscience Reports · doi:10.1042/bsr20222230 · Cited by 14 · see citing works
The Role of NLRP3 Inflammasomes in Trained Immunity
Lee, G., Ahn, H., Lee, G., & Lee, G. (2023) · Frontiers in Bioscience-Landmark · doi:10.31083/j.fbl2809210 · Cited by 14 · see citing works
“H3K9me3 and H3K27me3 were found in the promoter of glucose-6-phosphate dehydrogenase ( G6PD ), a pentose phosphate pathway-related gene that suppresses ROS generation [65,66].”
BackgroundLiu, H., Zhao, H., Zhang, Y., Li, X., Zuo, Y., Wu, Z., Jin, K., Xian, W., Wang, W., Ning, W., et al. (2024) · Journal of Integrative Plant Biology · doi:10.1111/jipb.13765 · Cited by 15 · see citing works
“…recognized role of DNA methylation and H3K27me3 as signi fi cant epigenetic mechanisms in fl uencing gene activity (Wang et al., 2009; Moore et al., 2013; Cai et al., 2021; Mattei et al., 2022), it is inferred that these unique gene families may be instrumental in modulating gene expression to…”
Self-citationTang, Y., Chen, F., Fang, G., Zhang, H., Zhang, Y., Zhu, H., Zhang, X., Han, Y., Cao, Z., Guo, F., et al. (2024) · The EMBO Journal · doi:10.1038/s44318-024-00257-4 · Cited by 14 · see citing works
“Next, a Venn plot analysis we made to specify the peaks shared by both TEAD4 and H3K27me3 identi fi ed 761 and 235 co-existing peaks in control and GLUP groups, respectively (Fig.”
InfluentialSelf-citationHofbauer, L., Pleyer, L., Reiter, F., Schleiffer, A., Vlasova, A. V., Serebreni, L., Huang, A., & Stark, A. (2024) · Molecular Cell · doi:10.1016/j.molcel.2024.10.041 · Cited by 14 · see citing works
Molecular and epigenetic basis of heat stress responses and acclimatization in plants
Tiwari, A., Rai, S. P., Rai, K. K., Tiwari, A. A., & Pandey, N. (2022) · The Nucleus · doi:10.1007/s13237-022-00400-8 · Cited by 13 · see citing works
“, trimethylation of histone H3 lysine) is an important histone mark of repression of gene expression [9].”
BackgroundUncovering the whole genome silencers of human cells via Ss-STARR-seq
Zhu, X., Huang, L., Wang, C., Li, G., Deng, B., Kong, D., Wang, X., Chang, R., Gu, Y., Wen, Q., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-55852-8 · Cited by 12 · see citing works
“To explore whether silencers undergo speci fi c chromatin modi fi cations, we initially validated the reported histone modi fi cation H3K27me3 13,39 , which serves as a predictor for silencers, along with the enrichment of the typical active histone modi fi cation H3K27ac in silencers, enhancers, and…”
InfluentialSelf-citationNucleoli in epithelial cell collectives respond to tumorigenic, spatial, and mechanical cues
Jaecker, F. F., Almeida, J. A., Krull, C. M., & Pathak, A. (2022) · Molecular Biology of the Cell · doi:10.1091/mbc.e22-02-0070 · Cited by 11 · see citing works
“To understand whether chromatin compaction responds to mechanical cues, we stained and imaged for the histone H3K27me3, an indicator of compacted chromatin (Cai et al. , 2021).”
DNA methylation insulates genic regions from CTCF loops near nuclear specklesPreprint
Roseman, S. A., Siegenfeld, A. P., Lee, C., Lue, N. Z., Waterbury, A. L., & Liau, B. B. (2025) · bioRxiv · doi:10.7554/elife.102930 · Cited by 17 · see citing works
“…CTCF peaks by the number of different partners they interact with and called those with the most partners ‘highly looping’, analogously to how superenhancers or supersilencers were previously characterized ( Figure 2B and C , Figure 2—figure supplement 1B ; Cai et al., 2021 ; Hnisz et al., 2013 ).”
An Expanded Registry of Candidate cis-Regulatory Elements for Studying Transcriptional RegulationPreprint
Moore, J. E., Pratt, H., Fan, K., Phalke, N. N., Fisher, J., Elhajjajy, S. I., Andrews, G., Gao, M., Shedd, N., Fu, Y., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.12.26.629296 · Cited by 13 · see citing works
Gene regulatory landscape dissected by single-cell four-omics sequencing
Chen, Y., Liu, Z., Xu, H., Liu, J., Wang, M., Chi, Y., LIANG, B., Liu, M., Peng, Y., Ge, H., et al. (2026) · Nature · doi:10.1038/s41586-026-10322-z · Cited by 12 · see citing works
“To identify 2D clusters along the linear genome, we adapted a method originally developed to define H3K27me3-rich regions 94 .”
Edrei, Y., Levy, R., Kaye, D., Marom, A., Radlwimmer, B., & Hellman, A. (2023) · Genome biology · doi:10.1186/s13059-023-03094-6 · Cited by 12 · see citing works
O‐GlcNAc regulates anti‐fibrotic genes in lung fibroblasts through EZH2
Wu, Q. P., Vang, S., Zhou, J. Q., Krick, S., Barnes, J. W., & Sanders, Y. Y. (2024) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.18191 · Cited by 11 · see citing works
“30 EZH2 is the catalytic subunit of polycomb-repressive complex 2 (PRC2) that represses transcription.”
BackgroundZhang, Y., Chen, K., Tang, S. C., Cai, Y., Niibori-Nambu, A., See, Y. X., Fu, C., Raju, A., Lebeau, B., Ling, Z., et al. (2024) · Nature Structural & Molecular Biology · doi:10.1038/s41594-024-01391-7 · Cited by 16 · see citing works
Self-citation
- Authors
- Cai, Y., Zhang, Y., Loh, Y. P., Tng, J. Q., Lim, M. C., Cao, Z., Raju, A., Lieberman Aiden, E., Li, S., Manikandan, L., Tergaonkar, V., Tucker-Kellogg, G., & Fullwood, M. J.
- Affiliations
- National University of Singapore (SG)
- Agency for Science, Technology and Research (SG)
- Corresponding author
- Fullwood, Melissa Jane
- ORCID
- Venue
- Nature Communications
- Published
- 2021-01-29
- Volume
- 12
- Issue
- 1
- Pages
- 719-719
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC7846766
- OpenAlex
- W3124680305
- Cited by
- 321
- References
- 90
- Citations by year
- 2026: 49 · 2025: 65 · 2024: 79 · 2023: 58 · 2022: 52 · 2021: 17
- FWCI
- 16.56
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- National University of Singapore (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Research Foundation Singapore (NRF-CRP17-2017-02)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- H3K27me3, gene silencing, chromatin interactions, gene expression inhibition, H3K27ac, cell identity, xenograft tumor growth, polycomb repressive complex 2
- MeSH terms
- Chromatin Immunoprecipitation Sequencing, RNA-Seq, Animals, Chromatin, Female, Fibroblast Growth Factors, Histones, Humans, Insulin-Like Growth Factor II, Neoplasms, Gene Expression Regulation, Neoplastic, Xenograft Model Antitumor Assays, Silencer Elements, Transcriptional, Cell Line, Tumor, Mice, Gene Knockdown Techniques, Gene Knockout Techniques, Epigenetic Repression
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