Deletion of Polycomb Repressive Complex 2 From Mouse Intestine Causes Loss of Stem Cells

Koppens, Martijn A.J.; Bounova, Gergana; Gargiulo, Gaetano; Tanger, Ellen; Janssen, Hans; Cornelissen-Steijger, Paulien; Blom, Marleen; Song, Ji‐Ying; Wessels, Lodewyk; Lohuizen, Maarten van

doi:10.1053/j.gastro.2016.06.020

Cited by 73 publications

(100 citation statements)

References 42 publications

(41 reference statements)

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“…The enzymatic activity of this complex mediates the trimethylation of lysine 27 on histone H3 (H3K27me3) and leads to transcriptional repression of target genes (38,39). In a recently reported study, EED was found to regulate intestinal homeostasis, and EED KO mice showed defects in stem cell proliferation and lineage differentiation in the steady state (22,24). This phenotype makes this mouse model impractical for studying the role of PRC2 in colitis.…”

Section: Discussionmentioning

confidence: 99%

“…Such epithelial defects were detected in EED-depleted mice, but not in EZH2 KO mice, an effect likely due to the functional redundancy between EZH2 and EZH1 (24). However, EZH2 has higher enzymatic activity than EZH1 and is more frequently dysregulated in tumors compared with other components of PRC2, suggesting some unique functional properties (24). Interestingly, a study applying a rank-based expression profile comparative algorithm between UC patients and siRNA-treated cells identified EZH2 as one of the top candidates for involvement in IBD (25).…”

mentioning

confidence: 91%

“…EED deficiency has been observed to impair stem cell proliferation and lead to abnormal secretory lineage commitment. Such epithelial defects were detected in EED-depleted mice, but not in EZH2 KO mice, an effect likely due to the functional redundancy between EZH2 and EZH1 (24). However, EZH2 has higher enzymatic activity than EZH1 and is more frequently dysregulated in tumors compared with other components of PRC2, suggesting some unique functional properties (24).…”

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confidence: 96%

“…This complex comprises the methyltransferases EZH1 or EZH2, as well as the structural proteins EED, SUZ12, and RBBP7/4 (21). Recent studies have revealed that PRC2 activity is required for intestinal epithelial homeostasis (22)(23)(24). EED deficiency has been observed to impair stem cell proliferation and lead to abnormal secretory lineage commitment.…”

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confidence: 99%

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Epithelial EZH2 serves as an epigenetic determinant in experimental colitis by inhibiting TNFα-mediated inflammation and apoptosis

Liu

Peng

Sun

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Epithelial barrier disruption is a major cause of inflammatory bowel disease (IBD); however, the mechanism through which epigenetic regulation modulates intestinal epithelial integrity remains largely undefined. Here we show that EZH2, the catalytic subunit of polycomb repressive complex (PRC2), is indispensable for maintaining epithelial cell barrier integrity and homeostasis under inflammatory conditions. In accordance with reduced EZH2 expression in patients, the inactivation of EZH2 in IECs sensitizes mice to DSS-and TNBSinduced experimental colitis. Conversely, EZH2 overexpression in the intestinal epithelium renders mice more resistant to colitis. Mechanistically, the genes encoding TRAF2/5 are held in a finely tuned bivalent status under inflammatory conditions. EZH2 deficiency potentiates the expression of these genes to enhance TNFα-induced NF-κB signaling, thereby leading to uncontrolled inflammation. More importantly, we show that EZH2 depletion compromises the protective role of NF-κB signaling in cell survival by directly up-regulating ITCH, a well-known E3 ligase that degrades the c-FLIP protein. Thus, our findings highlight an epigenetic mechanism by which EZH2 integrates the multifaceted effects of TNFα signaling to promote the inflammatory response and apoptosis in colitis.colitis | EZH2 | TNFα | NF-κB | ITCH

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Section: Discussionmentioning

confidence: 99%

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confidence: 91%

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confidence: 96%

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confidence: 99%

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Epithelial EZH2 serves as an epigenetic determinant in experimental colitis by inhibiting TNFα-mediated inflammation and apoptosis

Liu

Peng

Sun

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Accordingly, DNA methylation patterns are very similar between adult ISCs and terminally differentiated enterocytes (10–12). Loss of essential components of the Polycomb Repressive Complex 2, which positions the H3K27me3 mark, in the adult ISCs leads to cell cycle arrest and spontaneous differentiation towards the secretory lineage, yet has little effect on enterocyte specific differentiation program (13–15). Consistently, H3K27me3 patterns are very similar between adult ISCs and enterocytes (14).…”

Section: Introductionmentioning

confidence: 99%

Dynamic changes in chromatin states during specification and differentiation of adult intestinal stem cells

Kazakevych

Sayols

Messner

et al. 2017

Nucleic Acids Research

106

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Epigenetic mechanisms, including chromatin structure, chromatin dynamics and histone modifications play an important role for maintenance and differentiation of pluripotent embryonic stem cells. However, little is known about the molecular mechanisms of adult stem cell specification and differentiation. Here, we used intestinal stem cells (ISCs) as a model system to reveal the epigenetic changes coordinating gene expression programs during these processes. We found that two distinct epigenetic mechanisms participate in establishing the transcriptional program promoting ISC specification from embryonic progenitors. A large number of adult ISC signature genes are targets of repressive DNA methylation in embryonic intestinal epithelial progenitors. On the other hand, genes essential for embryonic development acquire H3K27me3 and are silenced during ISC specification. We also show that the repression of ISC signature genes as well as the activation of enterocyte specific genes is accompanied by a global loss of H2A.Z during ISCs differentiation. Our results reveal that, already during ISC specification, an extensive remodeling of chromatin both at promoters and distal regulatory elements organizes transcriptional landscapes operating in differentiated enterocytes, thus explaining similar chromatin modification patterns in the adult gut epithelium.

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PRC2‐complex related dysfunction in overgrowth syndromes: A review of EZH2, EED, and SUZ12 and their syndromic phenotypes

Cyrus

Burkardt

Weaver

et al. 2019

American J of Med Genetics Pt C

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The EZH2, EED, and SUZ12 genes encode proteins that comprise core components of the polycomb repressive complex 2 (PRC2), an epigenetic “writer” with H3K27 methyltransferase activity, catalyzing the addition of up to three methyl groups on histone 3 at lysine residue 27 (H3K27). Partial loss‐of‐function variants in genes encoding the EZH2 and EED subunits of the complex lead to overgrowth, macrocephaly, advanced bone age, variable intellectual disability, and distinctive facial features. EZH2‐associated overgrowth, caused by constitutional heterozygous mutations within Enhancer of Zeste homologue 2 (EZH2), has a phenotypic spectrum ranging from tall stature without obvious intellectual disability or dysmorphic features to classical Weaver syndrome (OMIM #277590). EED‐associated overgrowth (Cohen–Gibson syndrome; OMIM #617561) is caused by germline heterozygous mutations in Embryonic Ectoderm Development (EED), and manifests overgrowth and intellectual disability (OGID), along with other features similar to Weaver syndrome. Most recently, rare coding variants in SUZ12 have also been described that present with clinical characteristics similar to the previous two syndromes. Here we review the PRC2 complex and clinical syndromes of OGID associated with core components EZH2, EED, and SUZ12.

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Deletion of Polycomb Repressive Complex 2 From Mouse Intestine Causes Loss of Stem Cells

Cited by 73 publications

References 42 publications

Epithelial EZH2 serves as an epigenetic determinant in experimental colitis by inhibiting TNFα-mediated inflammation and apoptosis

Epithelial EZH2 serves as an epigenetic determinant in experimental colitis by inhibiting TNFα-mediated inflammation and apoptosis

Dynamic changes in chromatin states during specification and differentiation of adult intestinal stem cells

PRC2‐complex related dysfunction in overgrowth syndromes: A review of EZH2, EED, and SUZ12 and their syndromic phenotypes

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