Acquired Tissue-Specific Promoter Bivalency Is a Basis for PRC2 Necessity in Adult Cells
Open accessAbstract
Bivalent promoters in embryonic stem cells (ESCs) carry methylation marks on two lysine residues, K4 and K27, in histone3 (H3). K4me2/3 is generally considered to promote transcription, and Polycomb Repressive Complex 2 (PRC2) places K27me3, which is erased at lineage-restricted genes when ESCs differentiate in culture. Molecular defects in various PRC2 null adult tissues lack a unifying explanation. We found that epigenomes in adult mouse intestine and other self-renewing tissues show fewer and distinct bivalent promoters compared to ESCs. Groups of tissue-specific genes that carry bivalent marks are repressed, despite the presence of promoter H3K4me2/3. These are the predominant genes de-repressed in PRC2-deficient adult cells, where aberrant expression is proportional to the H3K4me2/3 levels observed at their promoters in wild-type cells. Thus, in adult animals, PRC2 specifically represses genes with acquired, tissue-restricted promoter bivalency. These findings provide new insights into specificity in chromatin-based gene regulation.
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Deficiency in Eed and loss of H3K27me3 led to up-regulation of known PRC2 targets such as Tbx15 and Hoxd8, but did not affect expression of genes defining microglia lineage identity or genes characteristic of pro-inflammatory activation.
“The deficiency in Eed and the ensuing loss of H3K27me3 led to the up-regulation of several known PRC2 targets, such as Tbx15 and Hoxd830,31 (Fig. 5g,h, Supplementary Fig. 11f,g, Supplementary Table 8,9), but did not affect the expression of genes that define microglia lineage identity (Supplementary Fig. 11f,g, Supplementary Table 8,9) or genes characteristic of microglia pro-inflammatory”
From Epigenetic regulation of brain region-specific microglia clearance activity (2018) · cites this paper as [30]
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InfluentialHigh-Resolution Profiling of Histone Methylations in the Human Genome
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MethodInfluentialA bivalent chromatin structure marks key developmental genes in embryonic stem cells
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The Polycomb complex PRC2 and its mark in life
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Polycomb complexes repress developmental regulators in murine embryonic stem cells
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Chromatin signatures of pluripotent cell lines
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Tissue‐specific and inducible Cre‐mediated recombination in the gut epithelium
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A clustering approach for identification of enriched domains from histone modification ChIP-Seq data
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MethodInfluentialHyperdynamic Plasticity of Chromatin Proteins in Pluripotent Embryonic Stem Cells
Meshorer, E., Yellajoshyula, D., George, E. M., Scambler, P. J., Brown, D. T., & Misteli, T. (2006) · Developmental Cell · doi:10.1016/j.devcel.2005.10.017 · Cited by 1,008 · cited 2× · see citing works
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“Unmethylated CpG islands (CGI) are thought to be an important means of PRC2 recruitment (Mohn et al., 2008; Riising et al., 2014; Voigt et al., 2013) and could have a role at ISC-specific genes, such as Lgr5, that acquire H3K27me3 during crypt differentiation.”
InfluentialSuz12 is essential for mouse development and for EZH2 histone methyltransferase activity
Pasini, D., Bracken, A. P., Jensen, M. R., Denchi, E. L., & Helin, K. (2004) · The EMBO Journal · doi:10.1038/sj.emboj.7600402 · Cited by 910 · cited 2× · see citing works
“Mammalian PRC2 contains the enzyme EZH1 or EZH2 and two proteins—EED and SUZ12—that are required to assemble the active complex (Kuzmichev et al., 2002; Pasini et al., 2004).”
The Transcriptional and Epigenomic Foundations of Ground State Pluripotency
Marks, H., Kalkan, T., Menafra, R., Denissov, S., Jones, K. A., Hofemeister, H., Nichols, J., Kranz, A., Stewart, A., Smith, A. G., et al. (2012) · Cell · doi:10.1016/j.cell.2012.03.026 · Cited by 881 · cited 3× · see citing works
“, 2008), and only 31% of genes showing bivalency in the presence of serum do so under these ‘‘2i conditions,’’ where H3K27me3 levels are significantly lower at many genes (Marks et al., 2012).”
InfluentialA double take on bivalent promotersPreprint
Voigt, P., Tee, W., & Reinberg, D. (2013) · Genes & Development · doi:10.1101/gad.219626.113 · Cited by 811 · cited 3× · see citing works
“Unmethylated CpG islands (CGIs) are thought to be an important means of PRC2 recruitment (Mohn et al., 2008; Riising et al., 2014; Voigt et al., 2013) and could have a role at ISC-specific genes, such as Lgr5, that acquire H3K27me3 during crypt differentiation.”
Distinct epigenomic landscapes of pluripotent and lineage-committed human cells
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“H3K27me3 domains also appear or expand in differentiated cells concomitant with gene silencing (Hawkins et al., 2010), which suggests that PRC2mediated repression, established during development, controls spatiotemporal gene activity.”
Transcription Factor Achaete Scute-Like 2 Controls Intestinal Stem Cell Fate
van der Flier, L. G., van Gijn, M. E., Hatzis, P., Kujala, P., Haegebarth, A., Stange, D. E., Begthel, H., van den Born, M., Guryev, V., Oving, I. M., et al. (2009) · Cell · doi:10.1016/j.cell.2009.01.031 · Cited by 718 · see citing works
Cistrome: an integrative platform for transcriptional regulation studies
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“Aggregate read density profiles of H3K27me3, H3K4me3, and Plo2 were generated using SitePro (Liu et al., 2011) and ggplot2 tools in the R package.”
The Polycomb Group Protein Suz12 Is Required for Embryonic Stem Cell Differentiation
Pasini, D., Bracken, A. P., Hansen, J. B., Capillo, M., & Helin, K. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.01432-06 · Cited by 696 · cited 1× · see citing works
“In PRC2-deficient ESCs, some genes ordinarily restricted to specific tissuesmay activate prematurely (Boyer et al., 2006; Pasini et al., 2007).”
Cui, K., Zang, C., Roh, T., Schones, D. E., Childs, R. W., Peng, W., & Zhao, K. (2009) · Cell stem cell · doi:10.1016/j.stem.2008.11.011 · Cited by 620 · cited 2× · see citing works
“However, promoter bivalency and its functional significance are not readily evident in fetal or adult somatic cells (Alder et al., 2010; Cui et al., 2009; Lien et al., 2011; Mohn et al., 2008) and may be confined to early mammalian embryos (Voigt et al.”
Genome-wide chromatin state transitions associated with developmental and environmental cues
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“However, ESCs and early embryos have unique, globally permissive chro- matin (Meshorer et al., 2006; Zhu et al., 2013), and their regulatory processes may differ from those in adult tissues.”
Chromatin modifications as determinants of muscle stem cell quiescence and chronological aging
Liu, L., Cheung, T. H., Charville, G. W., Hurgo, B. M. C., Leavitt, T., Shih, J., Brunet, A., & Rando, T. A. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.05.043 · Cited by 544 · cited 1× · see citing works
“Although H3K4me2/3 has previously been noted at H3K27me3-bearing promoters in some fetal, adult, and ESCderived cells (Abraham et al., 2013; Barski et al., 2007; Liu et al., 2013; Mikkelsen et al., 2007), the distribution and functions of bivalency have not been established.”
Asymmetrically Modified Nucleosomes
Voigt, P., LeRoy, G., Drury, W. J., Zee, B. M., Son, J., Beck, D. B., Young, N. L., Garcia, B. A., & Reinberg, D. (2012) · Cell · doi:10.1016/j.cell.2012.09.002 · Cited by 457 · cited 1× · see citing works
“, 2006), where these nominally opposing marks appear on the same nucleosome in the same cells (Bernstein et al., 2006; Voigt et al., 2012).”
Shen, L., Shao, N., Liu, X., Maze, I. S., Feng, J., & Nestler, E. J. (2013) · PLoS ONE · doi:10.1371/journal.pone.0065598 · Cited by 403 · cited 4× · see citing works
“Differential ChIP signals were identified using DiffReps version 1.55.4 (Shen et al., 2013) and using H3K27me3-ChIP and ChIP-Input (background) with default parameters, FDR 0.001 as a cutoff, and negative binomial test for statistical analysis.”
MethodInfluentialGene Silencing Triggers Polycomb Repressive Complex 2 Recruitment to CpG Islands Genome Wide
Riising, E. M., Comet, I. V., Leblanc, B., Wu, X., Johansen, J. V., & Helin, K. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.06.005 · Cited by 402 · cited 1× · see citing works
“Because crypt cell replication is as vulnerable to PRC2 loss as other self-renewing tissues (Delgado-Olguı́n et al., 2012; Ezhkova et al., 2011; Schwarz et al., 2014; Xie et al., 2014), EZH2 inhibitors may induce intestinal toxicity.”
Ezhkova, E., Lien, W.-H., Stokes, N., Pasolli, H. A., Silva, J. M., & Fuchs, E. (2011) · Genes & Development · doi:10.1101/gad.2019811 · Cited by 357 · cited 12× · see citing works
“Gene expression in PRC2-deficient skin and blood cells (Ezhkova et al., 2011; Xie et al., 2014) had been determined on Affymetrix Mouse Genome 430 2.”
InfluentialThe Murine Polycomb Group Protein Eed Is Required for Global Histone H3 Lysine-27 Methylation
Montgomery, N. D., Yee, D., Chen, A., Kalantry, S., Chamberlain, S. J., Otte, A. P., & Magnuson, T. (2005) · Current Biology · doi:10.1016/j.cub.2005.04.051 · Cited by 345 · cited 2× · see citing works
“PRC2 Loss In Vivo Impairs Cell Proliferation and Preferentially Activates Genes with Acquired TissueRestricted H3K27me3 To define this dependency, we disrupted Eed, a gene required for PRC2 assembly and catalytic activity (Montgomery et al., 2005).”
Xie, H., Xu, J., Hsu, J. H.-R., Nguyen, M., Fujiwara, Y., Peng, C., & Orkin, S. H. (2013) · Cell stem cell · doi:10.1016/j.stem.2013.10.001 · Cited by 320 · cited 19× · see citing works
“Gene expression in PRC2-deficient skin and blood cells (Ezhkova et al., 2011; Xie et al., 2014) had been determined on Affymetrix Mouse Genome 430 2.”
InfluentialSelf-citationDelgado-Olguı́n, P., Huang, Y., Li, X., Christodoulou, D. C., Seidman, C. E., Seidman, J. G., Tarakhovsky, A., & Bruneau, B. G. (2012) · Nature Genetics · doi:10.1038/ng.1068 · Cited by 260 · cited 3× · see citing works
“Because crypt cell replication is as vulnerable to PRC2 loss as other self-renewing tissues (Delgado-Olguı́n et al., 2012; Ezhkova et al., 2011; Schwarz et al., 2014; Xie et al., 2014), EZH2 inhibitors may induce intestinal toxicity.”
Broadly permissive intestinal chromatin underlies lateral inhibition and cell plasticity
Kim, T.-H., Li, F., Ferreiro-Neira, I., Ho, L.-L., Luyten, A., Nalapareddy, K., Long, H., Verzi, M., & Shivdasani, R. A. (2014) · Nature · doi:10.1038/nature12903 · Cited by 257 · cited 3× · see citing works
“Isolated crypt epithelium was disaggregated over 30 min in 4% TrypLE solution (Invitrogen) at 37 C, and GFPhi cells were isolated by flow cytometry (BD FACSAria II SORP), as described previously (Kim et al., 2014).”
MethodInfluentialSelf-citationHidalgo, I., Herrera-Merchan, A., Ligos, J. M., Carramolino, L., Nuñez, J., Martinez, F., Dominguez, O., Torres, M., & Gonzalez, S. (2012) · Cell Stem Cell · doi:10.1016/j.stem.2012.08.001 · Cited by 222 · cited 4× · see citing works
“It is worth noting in this light that, although deletion of Cdkn2a restores the proliferative potential of PRC2-deficient blood cells (Hidalgo et al., 2012), other defects remain, leading to stem-cell exhaustion, for example (Xie et al., 2014).”
InfluentialJuan, A. H., Derfoul, A., Feng, X., Ryall, J. G., Dell’Orso, S., Pasut, A., Zare, H., Simone, J. M., Rudnicki, M. A., & Sartorelli, V. (2011) · Genes & Development · doi:10.1101/gad.2027911 · Cited by 218 · cited 2× · see citing works
“…skin, and other tissues is attributed to the activation of genes that inhibit the cell cycle, such as Cdkn2a, because concomitant loss of single Cdkn genes rescues the overt defect (Delgado-Olguı́n et al., 2012; Ezhkova et al., 2011; Hidalgo et al., 2012; Juan et al., 2011; Xie et al., 2014).”
Lien, W.-H., Guo, X., Polak, L., Lawton, L. N., Young, R. A., Zheng, D., & Fuchs, E. (2011) · Cell Stem Cell · doi:10.1016/j.stem.2011.07.015 · Cited by 199 · cited 6× · see citing works
“Differential Bivalent Domains in Adult Mouse Tissues (A) H3K27me3 (amber), mRNA (green), and promoter H3K4me3 (blue) profiles in adult intestinal villus, blood (Hasemann et al., 2014), and skin (Lien et al., 2011) cells.”
InfluentialFaust, C. J., Lawson, K. A., Schork, N. J., Thiel, B., & Magnuson, T. (1998) · Development · doi:10.1242/dev.125.22.4495 · Cited by 198 · see citing works
Bettess, M. D., Dubois, N. C., Murphy, M., Dubey, C., Roger, C., Robine, S., & Trumpp, A. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.17.7868-7878.2005 · Cited by 149 · cited 2× · see citing works
“…in these intact villi (Figures 4A and S5B, arrowheads) indicates that they originate in cells that escaped biallelic Eed deletion; the selective advantage of such wild-type crypts over mutant crypts is well established in other mouse models (Bettess et al., 2005; van der Flier et al., 2009).”
Identifying Positioned Nucleosomes with Epigenetic Marks in Human from ChIP-Seq
Zhang, Y., Shin, H., Song, J. S., Lei, Y., & Liu, X. S. (2008) · BMC Genomics · doi:10.1186/1471-2164-9-537 · Cited by 138 · cited 1× · see citing works
“Nucleosomes carrying H3K4me3 or H3K27me3 in crypt progenitors andH3K4me3 in adult villi were determinedwith nucleosome positioning from sequencing (NPS) (Zhang et al., 2008), using default parameters.”
Das, P. P., Shao, Z., Beyaz, S., Apostolou, E., Pinello, L., Angeles, A. D. L., O’Brien, K., Atsma, J. M., Fujiwara, Y., Nguyen, M., et al. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.11.011 · Cited by 127 · cited 2× · see citing works
“…verify this late acquisition of H3K27me3 in adult tissues, we pooled all putative PRC2 targets identified in various ChIP-seq analyses of H3K27me3 (Das et al., 2014; Shpargel et al., 2014; Subramanian et al., 2013) or SUZ12 (Riising et al., 2014) in undifferentiated ESCs grown in serum or 2i…”
MethodSelf-citationShpargel, K. B., Starmer, J., Yee, D., Pohlers, M., & Magnuson, T. (2014) · PLoS Genetics · doi:10.1371/journal.pgen.1004507 · Cited by 124 · cited 2× · see citing works
“…this late acquisition of H3K27me3 in adult tissues, we pooled all putative PRC2 targets identified in various ChIP-seq analyses of H3K27me3 (Das et al., 2014; Shpargel et al., 2014; Subramanian et al., 2013) or SUZ12 (Riising et al., 2014) in undifferentiated ESCs grown in serum or 2i conditions.”
MethodEzh2 is required for neural crest-derived cartilage and bone formation
Schwarz, D. F., Varum, S., Zemke, M., Schöler, A., Baggiolini, A., Draganova, K., Koseki, H., Schübeler, D., & Sommer, L. (2014) · Development · doi:10.1242/dev.094342 · Cited by 116 · cited 1× · see citing works
“Because crypt cell replication is as vulnerable to PRC2 loss as other self-renewing tissues (Delgado-Olguı́n et al., 2012; Ezhkova et al., 2011; Schwarz et al., 2014; Xie et al., 2014), EZH2 inhibitors may induce intestinal toxicity.”
Alder, O., Lavial, F., Helness, A., Brookes, E., Pinho, S., Chandrashekran, A., Arnaúd, P., Pombo, A., O’Neill, L. P., & Azuara, V. (2010) · Development · doi:10.1242/dev.048363 · Cited by 115 · cited 1× · see citing works
“However, promoter bivalency and its functional significance are not readily evident in fetal or adult somatic cells (Alder et al., 2010; Cui et al., 2009; Lien et al., 2011; Mohn et al., 2008) and may be confined to early mammalian embryos (Voigt et al., 2013).”
Hasemann, M. S., Lauridsen, F. K. B., Waage, J., Jakobsen, J. S., Frank, A.-K., Schuster, M. B., Rapin, N., Bagger, F. O., Hoppe, P. S., Schroeder, T., et al. (2014) · PLoS Genetics · doi:10.1371/journal.pgen.1004079 · Cited by 103 · cited 3× · see citing works
“Differential Bivalent Domains in Adult Mouse Tissues (A) H3K27me3 (amber), mRNA (green), and promoter H3K4me3 (blue) profiles in adult intestinal villus, blood (Hasemann et al., 2014), and skin (Lien et al., 2011) cells.”
Subramanian, V., Mazumder, A., Surface, L. E., Butty, V. L., Fields, P., Alwan, A., Sosa, L. T., Thai, K. K., Levine, S. S., Bathe, M., et al. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003725 · Cited by 62 · cited 3× · see citing works
“…genes and bivalent domains in adult tissues are also targets of PRC2 regulation in early embryos, we used unsupervised k-means clustering, as described earlier (k = 5), to identify genes heavily marked in undifferentiated ESCs grown in the presence of serum (Subramanian et al., 2013).”
Dynamic regulation of epigenomic landscapes during hematopoiesis
Abraham, B. J., Cui, K., Tang, Q., & Zhao, K. (2013) · BMC Genomics · doi:10.1186/1471-2164-14-193 · Cited by 55 · cited 1× · see citing works
“Although H3K4me2/3 has previously been noted at H3K27me3-bearing promoters in some fetal, adult, and ESCderived cells (Abraham et al., 2013; Barski et al., 2007; Liu et al., 2013; Mikkelsen et al., 2007), the distribution and functions of bivalency have not been established.”
BGDB: a database of bivalent genes
Li, Q., Lian, S., Dai, Z., Xiang, Q., & Dai, X. (2013) · Database · doi:10.1093/database/bat057 · Cited by 21 · cited 2× · see citing works
“(C and D) Overlap of genes carrying H3K27me3 (C) or regarded as bivalent in ESCs (D) (Li et al., 2013), with those marked in the adult mouse duodenum.”
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Tales from the crypt: new insights into intestinal stem cells
Gehart, H., & Clevers, H. C. (2018) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-018-0081-y · Cited by 984 · see citing works
The interplay of epigenetic marks during stem cell differentiation and development
Atlasi, Y., & Stunnenberg, H. G. (2017) · Nature Reviews Genetics · doi:10.1038/nrg.2017.57 · Cited by 569 · see citing works
Chemosensitive Relapse in Small Cell Lung Cancer Proceeds through an EZH2-SLFN11 Axis
Gardner, E. E., Lok, B. H., Schneeberger, V. E., Desmeules, P., Miles, L. A., Arnold, P. K., Ni, A., Khodos, I., de Stanchina, E., Nguyen, T. N., et al. (2017) · Cancer Cell · doi:10.1016/j.ccell.2017.01.006 · Cited by 527 · see citing works
“A shift in global repressive histonemethylationmay have pleiotropic effects on gene expression that manifest in a cell-line-specific manner (Jadhav et al., 2016).”
Epigenetic regulation of brain region-specific microglia clearance activity
Ayata, P., Badimon, A., Strasburger, H. J., Duff, M. K., Montgomery, S. E., Loh, Y.-H. E., Ebert, A., Pimenova, A. A., Ramirez, B. R., Chan, A. T., et al. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0192-3 · Cited by 460 · see citing works
Dynamics of BAF–Polycomb complex opposition on heterochromatin in normal and oncogenic states
Kadoch, C., Williams, R. T., Calarco, J. P., Miller, E. L., Weber, C. M., Braun, S. M. G., Pulice, J. L., Chory, E. J., & Crabtree, G. R. (2016) · Nature Genetics · doi:10.1038/ng.3734 · Cited by 291 · see citing works
Nakayama, R. T., Pulice, J. L., Valencia, A. M., McBride, M. J., McKenzie, Z. M., Gillespie, M. A. K., Ku, W. L., Teng, M., Cui, K., Williams, R. T., et al. (2017) · Nature Genetics · doi:10.1038/ng.3958 · Cited by 291 · see citing works
The SS18-SSX Fusion Oncoprotein Hijacks BAF Complex Targeting and Function to Drive Synovial Sarcoma
McBride, M. J., Pulice, J. L., Beird, H. C., Ingram, D. R., D’Avino, A. R., Shern, J. F., Charville, G. W., Hornick, J. L., Nakayama, R. T., Garcia-Rivera, E., et al. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.05.002 · Cited by 266 · see citing works
“, those downregulated upon SS18-SSX knockdown) revealed that changes in gene expression strongly correlate with baseline H3K4me3 levels at gene promoters in the presence of SS18-SSX (Figure S5I), consistent with previous findings in settings of PRC2 loss (Jadhav et al., 2016).”
BackgroundResultPRC2 is high maintenancePreprint
Yu, J.-R., Lee, C., Oksuz, O., Stafford, J. M., & Reinberg, D. (2019) · Genes & Development · doi:10.1101/gad.325050.119 · Cited by 248 · see citing works
“Bivalent promoters are also present in adult stem cells, albeit being fewer than and distinctive to those in ESCs (Jadhav et al. 2016).”
BackgroundPolycomb repressive complex 2 (PRC2) silences genes responsible for neurodegeneration
von Schimmelmann, M., Feinberg, P. A., Sullivan, J. M., Ku, S. M., Badimon, A., Duff, M. K., Wang, Z., Lachmann, A., Dewell, S., Ma'ayan, A., et al. (2016) · Nature Neuroscience · doi:10.1038/nn.4360 · Cited by 225 · see citing works
“The necessity of PRC2 for bivalent gene silencing in adult neurons is consistent with a similar role of PRC2 in bivalent gene suppression-mediated patterning of the tissue-specific gene expression patterns in the adult mouse intestine, blood, and skin cells 45 .”
Regulation, functions and transmission of bivalent chromatin during mammalian development
Macrae, T. A., Fothergill-Robinson, J., & Ramalho‐Santos, M. (2022) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-022-00518-2 · Cited by 186 · see citing works
Tug of war: adding and removing histone lysine methylation in Arabidopsis
Xiao, J. Y., Lee, U.-S., & Wagner, D. (2016) · Current Opinion in Plant Biology · doi:10.1016/j.pbi.2016.08.002 · Cited by 176 · see citing works
Reprogramming of the FOXA1 cistrome in treatment-emergent neuroendocrine prostate cancer
Baca, S. C., Takeda, D., Seo, J.-H., Hwang, J. H., Ku, S., Arafeh, R., Arnoff, T. E., Agarwal, S., Bell, C., O'Connor, E., et al. (2020) · Nature Communications · doi:10.1038/s41467-021-22139-7 · Cited by 142 · see citing works
Editing the Epigenome: Reshaping the Genomic Landscape
Holtzman, L., & Gersbach, C. A. (2018) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev-genom-083117-021632 · Cited by 143 · see citing works
“While H3K9 methylation often correlates with silent promoters (47, 49, 128), H3K27 methyl marks are often associated with developmentally or differentially regulated genes (40, 45, 77, 101, 135) and can be present on both active and inactive genes (45, 83, 103).”
BackgroundMitochondrial function and gastrointestinal diseases
Haque, P. S., Kapur, N., Barrett, T. A., & Theiss, A. L. (2024) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-024-00931-2 · Cited by 142 · see citing works
“For instance, in differentiated mouse IECs, ~200 ISC-specific genes exhibit increased methylation of histone H3 (H3K27me3), associated with the silencing of transcription 58 .”
Context-specific Polycomb mechanisms in development
Kim, J. J., & Kingston, R. (2022) · Nature reviews genetics · doi:10.1038/s41576-022-00499-0 · Cited by 114 · see citing works
Dynamic Competition of Polycomb and Trithorax in Transcriptional Programming
Kuroda, M. I., Kang, H., De, S., & Kassis, J. A. (2020) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-120219-103641 · Cited by 120 · see citing works
Parental nucleosome segregation and the inheritance of cellular identity
Escobar, T. M., Loyola, A., & Reinberg, D. (2021) · Nature Reviews Genetics · doi:10.1038/s41576-020-00312-w · Cited by 106 · see citing works
Liu, Y., Peng, J., Sun, T., Li, N., Zhang, L., Ren, J., Yuan, H., Kan, S., Pan‐Hammarström, Q., Li, X., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1700909114 · Cited by 102 · see citing works
“Previous work has revealed that PRC2 specifically represses genes with bivalent promoters in the adult intestine (23).”
Capdevila, C., Miller, J. D., Cheng, L., Kornberg, A. E., George, J. J., Lee, H., Botella, T., Moon, C. S., Murray, J. W., Lam, S., et al. (2024) · Cell · doi:10.1016/j.cell.2024.05.001 · Cited by 104 · see citing works
Petracovici, A., & Bonasio, R. (2021) · Molecular Cell · doi:10.1016/j.molcel.2021.03.038 · Cited by 91 · see citing works
Polycomb complexes PRC1 and their function in hematopoiesis
Vidal, M., & Starowicz, K. (2017) · Experimental Hematology · doi:10.1016/j.exphem.2016.12.006 · Cited by 83 · see citing works
Kazakevych, J., Sayols, S., Messner, B., Krienke, C., & Soshnikova, N. V. (2017) · Nucleic Acids Research · doi:10.1093/nar/gkx167 · Cited by 83 · see citing works
“Consistently, H3K27me3 patterns are very similar between adult ISCs and enterocytes (14).”
BackgroundMethodInfluentialLineage-specific canonical and non-canonical activity of EZH2 in advanced prostate cancer subtypes
Venkadakrishnan, V. B., Presser, A. G., Singh, R., Booker, M. A., Traphagen, N. A., Weng, K., Voss, N. C. E., Mahadevan, N. R., Mizuno, K., Puca, L., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-51156-5 · Cited by 84 · see citing works
Replicational Dilution of H3K27me3 in Mammalian Cells and the Role of Poised Promoters
Jadhav, U., Manieri, E., Nalapareddy, K., Madha, S., Chakrabarti, S., Wucherpfennig, K. W., Barefoot, M. E., & Shivdasani, R. A. (2020) · Molecular Cell · doi:10.1016/j.molcel.2020.01.017 · Cited by 81 · see citing works
“The consequences of PRC2 inactivity in mouse intestines (Jadhav et al., 2016) suggest that EZH and EED inhibitors will cause significant intestinal toxicity.”
BackgroundInfluentialSelf-citationAnnotation of chromatin states in 66 complete mouse epigenomes during development
van der Velde, A., Fan, K., Tsuji, J., Moore, J. E., Purcaro, M. J., Pratt, H., & Weng, Z. (2021) · Communications Biology · doi:10.1038/s42003-021-01756-4 · Cited by 67 · see citing works
DNMT and EZH2 inhibitors synergize to activate therapeutic targets in hepatocellular carcinoma
Zhang, L., Li, H., Shereda, R., Lu, Q., Weisenberger, D. J., O'Connell, C. L., Machida, K., An, W., Lenz, H., El-Khoueiry, A. B., et al. (2022) · Cancer Letters · doi:10.1016/j.canlet.2022.215899 · Cited by 75 · see citing works
Extensive Recovery of Embryonic Enhancer and Gene Memory Stored in Hypomethylated Enhancer DNA
Jadhav, U., Cavazza, A., Banerjee, K. K., Xie, H., O’Neill, N. K., Saenz-Vash, V., Herbert, Z. T., Madha, S., Orkin, S. H., Zhai, H., et al. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.02.024 · Cited by 71 · see citing works
“…histone mark H3K27me3 is associated in ESC and adult tissues with repressed promoters, especially those of morphogenetic and TF genes (Bernstein et al., 2006; Boyer et al., 2006; Jadhav et al., 2016), but H3K27me3 is typically absent at adult enhancers (Saxena et al., 2017; Zentner et al., 2011).”
InfluentialSelf-citationSATB2 preserves colon stem cell identity and mediates ileum-colon conversion via enhancer remodeling
Gu, W. Y., Wang, H., Huang, X., Kraiczy, J., Singh, P. N. P., Ng, C., Dağdeviren, S., Houghton, S., Pellón-Cárdenas, O., Lan, Y., et al. (2021) · Cell stem cell · doi:10.1016/j.stem.2021.09.004 · Cited by 73 · see citing works
Self-citationHallmarks of intestinal stem cells
Baulies, A., Angelis, N., & Li, V. S. W. (2020) · Development · doi:10.1242/dev.182675 · Cited by 66 · see citing works
Cell Fate and Developmental Regulation Dynamics by Polycomb Proteins and 3D Genome Architecture
Loubière, V., Martinez, A., & Cavalli, G. (2019) · BioEssays · doi:10.1002/bies.201800222 · Cited by 64 · see citing works
Court, F., & Arnaúd, P. (2016) · Oncotarget · doi:10.18632/oncotarget.13746 · Cited by 62 · see citing works
Grinat, J., Heuberger, J., Vidal, R. O., Goveas, N., Kosel, F., Berenguer, A., Kranz, A., Wulf-Goldenberg, A., Behrens, D., Melcher, B., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-20222-z · Cited by 62 · see citing works
Södersten, E., Toskas, K., Rraklli, V., Tiklová, K., Björklund, Å. K., Ringnér, M., Perlmann, T., & Holmberg, J. (2018) · Nature Communications · doi:10.1038/s41467-018-03538-9 · Cited by 52 · see citing works
Sui, B., Chen, D., Liu, W., Wu, Q. D., Tian, B., Li, Y., Hou, J., Liu, S., Xie, J., Jiang, H., et al. (2020) · Genome biology · doi:10.1186/s13059-020-02150-9 · Cited by 54 · see citing works
“consistent with a recent report that many H3K27me3 marks in adult mice is not related to transcriptional regulation [62].”
ResultHarvey, A. J., Caretti, G., Moresi, V., Renzini, A., & Adamo, S. (2019) · Stem Cell Reports · doi:10.1016/j.stemcr.2019.09.003 · Cited by 51 · see citing works
“Nevertheless, bivalency is not exclusive to stem or progenitor cells, because cells of restricted potency, including T cells, fibroblasts, and adult tissues, can also acquire de novo bivalency (Jadhav et al., 2016).”
BackgroundZenk, F. L., Fleck, J. S., Jansen, S. M. J., Kashanian, B., Eisinger, B., Santel, M., Dupré, J.-S., Camp, J. G., & Treutlein, B. (2024) · Nature Neuroscience · doi:10.1038/s41593-024-01652-0 · Cited by 53 · see citing works
“We next analyzed switching between H3K27me3 and H3K27ac, which are considered mutually exclusive as they are installed on the same histone H3 lysine 27 residue and rarely co-occur within a nucleosome 5,6,11 .”
Bivalent Epigenetic Control of Oncofetal Gene Expression in Cancer
Zaidi, S. K., Frietze, S. E., Gordon, J. A. R., Heath, J. L., Messier, T., Hong, D., Boyd, J. R., Kang, M., Imbalzano, A. N., Lian, J. B., et al. (2017) · Molecular and Cellular Biology · doi:10.1128/mcb.00352-17 · Cited by 48 · see citing works
“However, some PRC2-mediated, tissue-specific bivalency was observed independently of CpG islands (26).”
BackgroundHeppert, J. K., Davison, J. M., Kelly, C., Mercado, G. P., Lickwar, C. R., & Rawls, J. F. (2020) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-020-00357-6 · Cited by 43 · see citing works
Chu, L., Qu, Y.-X., An, Y., Hou, L., Li, J., Li, W., Fan, G., Song, B., Li, E., Zhang, L., et al. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-04601-6 · Cited by 45 · see citing works
“Indeed, studies in embryonic stem cells revealed the bivalency model, in which H3K4me3 and H3K27me3 often co-reside on the promoters of the developmental genes to transiently repress their expression [57].”
BackgroundKim, C.-K., Saxena, M., Maharjan, K., Song, J. J., Shroyer, K. R., Bialkowska, A. B., Shivdasani, R. A., & Yang, V. W. (2019) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2019.11.009 · Cited by 43 · see citing works
“These regions do not associate with upregulated genes.(24) Plot depicts the cumulative regulatory potential score, dashed line represents the background, and p-values denote the significance of UP or DOWN associations relative to the background.”
BackgroundMethodInfluentialSelf-citationTomizawa, S.-I., Kobayashi, Y., Shirakawa, T., Watanabe, K., Mizoguchi, K., Hoshi, I., Nakajima, K., Nakabayashi, J., Singh, S., Dahl, A., et al. (2018) · Development · doi:10.1242/dev.169102 · Cited by 41 · see citing works
“Bivalent chromatin is also prevalent in various adult cell types, including hematopoietic stem cells and intestinal epithelial cells, and appears to support tissuespecific epigenetic programs (Cui et al., 2009; Jadhav et al., 2016).”
BackgroundTranscriptional alterations in glioma result primarily from DNA methylation–independent mechanismsPreprint
Court, F., Boiteux, E. L., Fogli, A., Müller-Barthélémy, M., Vaurs‐Barrière, C., Chautard, E., Pereira, B., Biau, J., Kémény, J., Khalil, T., et al. (2019) · Genome Research · doi:10.1101/gr.249219.119 · Cited by 41 · see citing works
“To consider only robust methylation variations, CGI/promoters were classified as hypermethylated or hypomethylated only if they included at least two probes differentially methylated (gain or a loss of methylation) in their CGI.”
BackgroundInfluentialEpigenetics and Testicular Cancer: Bridging the Gap Between Fundamental Biology and Patient Care
Nicu, A.-T., Medar, C., Chifiriuc, M. C., Pîrcălăbioru, G. G., & Burlibaşa, L. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.861995 · Cited by 40 · see citing works
“Recently, bivalent marks have been found at the promoter of cancer related genes involved in the development of those tissues, suggesting a mechanism by which cancer cells reacquire some properties that are characteristic of undifferentiated, pluripotent cells (Jadhav et al., 2016).”
BackgroundNavigating the complexity of Polycomb repression: Enzymatic cores and regulatory modules
Tamburri, S., Rustichelli, S., Amato, S., & Pasini, D. (2024) · Molecular Cell · doi:10.1016/j.molcel.2024.07.030 · Cited by 40 · see citing works
McBride, M. J., & Kadoch, C. (2018) · The Journal of Pathology · doi:10.1002/path.5042 · Cited by 39 · see citing works
“In terminally differentiated cells, PcG proteins continue to repress genes of other tissue lineages to maintain the cellular identity [29].”
BackgroundSex Differences in the Epigenome: A Cause or Consequence of Sexual Differentiation of the Brain?
Gegenhuber, B., & Tollkühn, J. (2019) · Genes · doi:10.3390/genes10060432 · Cited by 40 · see citing works
“The Polycomb group proteins, which assemble into polycomb repressive complex 1 (PRC1) or 2 (PRC2), fulfill this dual reader-writer function and play well-known roles in stem cell differentiation, as well as cell-type maintenance [104,105].”
BackgroundSaxena, M., Roman, A. K. S., O’Neill, N. K., Sulahian, R., Jadhav, U., & Shivdasani, R. A. (2017) · Genes & Development · doi:10.1101/gad.308536.117 · Cited by 37 · see citing works
“…signals near type 1A enhancers in wild-type intestinal cells approximate those near expressed genes with low mRNA levels, are notably higher than the empiric genome background (Jadhav et al. 2016), and drew our attention because they are substantially elevated in Cdx2 − / − cells (Supplemental Fig.”
Self-citationLorzadeh, A., Romero-Wolf, M., Goel, A., & Jadhav, U. (2021) · Gastroenterology · doi:10.1053/j.gastro.2021.03.036 · Cited by 37 · see citing works
Self-citationGrindheim, J. M., Nicetto, D., Donahue, G., & Zaret, K. S. (2019) · Gastroenterology · doi:10.1053/j.gastro.2019.01.041 · Cited by 35 · see citing works
UTX Regulates Human Neural Differentiation and Dendritic Morphology by Resolving Bivalent Promoters
Tang, Q.-Y., Zhang, S.-F., Dai, S., Liu, C., Wang, Y.-Y., Du, H.-Z., Teng, Z., & Liu, C. (2020) · Stem Cell Reports · doi:10.1016/j.stemcr.2020.06.015 · Cited by 34 · see citing works
“UTX Acts as a Demethylase in Resolution and Activation of Bivalent Promoters during the Neural Differentiation of hESCs Because H3K27 methyltransferase complex PRC2 was associated with the generation of bivalency (Jadhav et al., 2016), we further assessed the effect of UTX loss on bivalent gene expression.”
BackgroundIntestinal Epithelial Organoids as Tools to Study Epigenetics in Gut Health and Disease
Kraiczy, J., & Zilbauer, M. (2019) · Stem Cells International · doi:10.1155/2019/7242415 · Cited by 31 · see citing works
“Similarly, distribution of the silencing H3K27me3 mark was overall unchanged between crypt and villus compartments [62].”
BackgroundTranscriptional memory in skeletal muscle. Don't forget (to) exercise
Beiter, T., Niess, A. M., & Moser, D. (2020) · Journal of Cellular Physiology · doi:10.1002/jcp.29535 · Cited by 29 · see citing works
“Intriguingly, hypomethylated CpG sites within regulatory regions may circumstantially be associated with “bivalent domains” of histone modifications, harboring both repressive marks, such as H3K27me3, and active marks, such as H3K4me3 (Jadhav et al., 2016; Kinkley et al., 2016; Sodersten et al., 2018; Weiner et al., 2…”
BackgroundPRC2 represses transcribed genes on the imprinted inactive X chromosome in mice
Maclary, E. T., Hinten, M., Harris, C. E., Sethuraman, S., Gayen, S., & Kalantry, S. (2017) · Genome biology · doi:10.1186/s13059-017-1211-5 · Cited by 30 · see citing works
“stem cells are derepressed in the absence of EED [69].”
BackgroundTerranova, C. J., Tang, M., Maitituoheti, M., Raman, A. T., Ghosh, A. K., Schulz, J., Amin, S. B., Orouji, E., Tomczak, K. J., Sarkar, S., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109410 · Cited by 30 · see citing works
METTL14 regulates chromatin bivalent domains in mouse embryonic stem cells
Mu, M., Li, X., Dong, L., Wang, J., Cai, Q., Hu, J., Wang, D., Zhao, P., Zhang, L., Zhang, D., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112650 · Cited by 29 · see citing works
Epigenetic Regulation of the Epithelial to Mesenchymal Transition in Lung Cancer
Roche, J., Gemmill, R. M., & Drabkin, H. A. (2017) · Cancers · doi:10.3390/cancers9070072 · Cited by 29 · see citing works
“This hypothesis fits with the PRC2 repressive activity on promoters with the activating mark H3K4me2/3 [96].”
BackgroundBaulies, A., Angelis, N., Foglizzo, V., Danielsen, E. T., Patel, H., Novellasdemunt, L., Kucharska, A., Carvalho, J., Nye, E. L., Coppi, P. D., et al. (2020) · Gastroenterology · doi:10.1053/j.gastro.2020.06.012 · Cited by 29 · see citing works
Fujimura, N., Kuzelova, A., Ebert, A., Strnad, H., Láchová, J., Machoň, O., Busslinger, M., & Kozmík, Z. (2017) · Developmental Biology · doi:10.1016/j.ydbio.2017.11.004 · Cited by 29 · see citing works
“In embryonic stem cells, early mouse embryo, and adult cells, subsets of H3K27me3 marks are present together with the active chromatin mark H3K4me3 on the regions called bivalent chromatin domains (Azuara et al., 2006; Bernstein et al., 2006; Jadhav et al., 2016; Rugg-Gunn et al., 2010).”
BackgroundInfluentialShivram, H., Le, S. V., & Iyer, V. R. (2019) · Genome Research · doi:10.1101/gr.238311.118 · Cited by 28 · see citing works
“3C) (Jadhav et al. 2016; Abou El Hassan et al. 2015).”
Epigenetic regulation of intestinal stem cell differentiation
Verzi, M. P., & Shivdasani, R. A. (2020) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00084.2020 · Cited by 27 · see citing works
Self-citationKashima, K., Kawai, T., Nishimura, R., Shiwa, Y., Urayama, K. Y., Kamura, H., Takeda, K., Aoto, S., Ito, A. M., Matsubara, K., et al. (2021) · Scientific Reports · doi:10.1038/s41598-021-83016-3 · Cited by 26 · see citing works
Bivalent chromatin instructs lineage specification during hematopoiesis
Yagi, M., Bonilla, G. M., Hoetker, M. S., Tsopoulidis, N., Horng, J. E., Haggerty, C., Meissner, A., Sadreyev, R. I., Hock, H. R., & Hochedlinger, K. (2025) · Cell · doi:10.1016/j.cell.2025.05.011 · Cited by 25 · see citing works
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Smith, R. J., Rao‐Bhatia, A., & Kim, T. (2017) · Wiley Interdisciplinary Reviews Developmental Biology · doi:10.1002/wdev.281 · Cited by 25 · see citing works
“Interestingly, 39% of genes that showed enrichment of H3K27me3 in villus cells are highly active in ISCs, including key ISC markers such as Lgr5 and Ascl2.”
BackgroundInfluentialToskas, K., Salmani, B. Y., Skiteva, O., Pasławski, W., Gillberg, L., Skara, V., Antoniou, E., Södersten, E., Svenningsson, P., Chergui, K., et al. (2022) · Science Advances · doi:10.1126/sciadv.abo1543 · Cited by 24 · see citing works
Dunn-Davies, H., Dudnakova, T., Nogara, A. M., Rodor, J., Thomas, A. C., Parish, E., Gautier, P. E., Meynert, A. M., Ulitsky, I., Madeddu, P. R., et al. (2024) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2024.102173 · Cited by 23 · see citing works
Carrasco, M. E., Thaler, R., Nardocci, G., Dudakovic, A., & van Wijnen, A. J. (2023) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2023.105155 · Cited by 22 · see citing works
“suggest that tissue-specific transcription factors recruit PRC2 to add H3K27me3 at gene loci to prevent aberrant gene expression (54, 55).”
BackgroundDiverse gene regulatory mechanisms mediated by Polycomb group proteins during neural development
Tsuboi, M., Hirabayashi, Y., & Gotoh, Y. (2019) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2019.07.003 · Cited by 22 · see citing works
Criqui, M., Qamra, A., Chu, T. W., Sharma, M., Tsao, J., Henry, D., Baršytė-Lovejoy, D., Arrowsmith, C. H., Winegarden, N. A., Lupien, M., et al. (2020) · eLife · doi:10.7554/elife.47333 · Cited by 22 · see citing works
H3K36 methylation regulates cell plasticity and regeneration in the intestinal epithelium
Swearingen, A. R., Meyer, A. R., Bussey-Sutton, C. R., O’Connor, E. S., Coradin, M., Coulombe, M., Riemondy, K. A., Potlapelly, S., Strahl, B. D., Hansson, G. C., et al. (2025) · Nature Cell Biology · doi:10.1038/s41556-024-01580-y · Cited by 21 · see citing works
“Although H3K27me3 profiles are similar between IECs 81 , perturbation of enzymes that add or remove H3K27 methylation has variable effects on IEC fate.”
Genetic and Epigenetic Regulation of Zebrafish Intestinal Development
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“Thus, the presence of the Ezh1 protein in the zebrafish intestine might compensate for the (partial) retention of the H3K27me3 mark on the intestinal tissue in ezh2−/− larvae and delay the observed phenotypes, although the loss of ezh2 is still ultimately lethal.”
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“However, because these predisposing marks diverge during tissue differentiation [6], it might be expected that some cancer-specific promoter methylation would also diverge between different cancers arising from different tissues.”
BackgroundATRX histone binding and helicase activities have distinct roles in neuronal differentiation
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“Like Mll1, polycomb PRC2 complexes have been implicated in the maintenance of intestinal stem and progenitor cells: their genetic ablation causes loss of stem cells and aberrant secretory differentiation (Chiacchiera et al, 2016; Jadhav et al, 2016).”
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“However, adult tissues still retain some bivalent, lineage-incompatible genes that require sustained Polycomb activity for proper repression (Jadhav et al., 2016, 2020).”
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“PRC2-regulated bivalent domains were also shown to be uniquely sensitive to dysregulation in adult intestine and haematopoietic tissues 98,99 .”
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“It is estimated that about 2000 genes are marked by H3K27me3 in both crypt and villus cells.(119) By cKO EED in the intestine, Chiacchiera et al.”
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“is postulated to poise developmentally crucial genes for later activation during differentiation, de novo acquired tissue-restricted bivalency results in repression of affected genes in intestine and expression of these genes in the brain [16,17].”
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Epigenetic control of cellular crosstalk defines gastrointestinal organ fate and function
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“9,14 Interestingly, although Eed -deletion does not impact ISCs, it increases the number of goblet cells and triggers an aberrant lineage commitment toward the secretory path.”
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Polycomb Assemblies Multitask to Regulate Transcription
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- Authors
- Jadhav, U., Nalapareddy, K., Saxena, M., O’Neill, N. K., Pinello, L., Yuan, G.-C., Orkin, S. H., & Shivdasani, R. A.
- Affiliations
- Brigham and Women's Hospital (US)
- Dana-Farber Cancer Institute (US)
- Harvard University (US)
- Boston Children's Hospital (US)
- Corresponding author
- Shivdasani, Ramesh A.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2016-06
- Volume
- 165
- Issue
- 6
- Pages
- 1389-1400
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4893000
- OpenAlex
- W2402793322
- Cited by
- 139
- References
- 49
- Citations by year
- 2026: 10 · 2025: 13 · 2024: 19 · 2023: 6 · 2022: 10 · 2021: 13 · 2020: 15 · 2019: 22 · 2018: 11 · 2017: 13 · 2016: 7
- FWCI
- 9.18
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Human Genome Research Institute (R01HG005085, K99HG008399)
- National Cancer Institute (P50CA127003)
- National Institute of Diabetes and Digestive and Kidney Diseases (U24DK085532, U01DK103152, R01DK081113, F32DK103453, U01DK085532)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Keywords
- bivalent promoters, polycomb repressive complex 2, H3K27me3, histone methylation, gene repression, tissue-specific gene regulation, intestinal epithelium, chromatin regulation, embryonic stem cells
- MeSH terms
- Animals, Cell Differentiation, Gene Expression Regulation, Histones, Intestinal Mucosa, Intestines, Lysine, Mice, Inbred C57BL, Promoter Regions, Genetic, DNA Methylation, Mice, Embryonic Stem Cells, Polycomb Repressive Complex 2
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