Mucosal genome-wide methylation changes in inflammatory bowel disease

Cooke, James C.; Hu, Zhang; Greger, Liliana; Silva, Ana-Luisa; Massey, Dunecan; Dawson, Claire; Metz, Andrew J.; Ibrahim, Ashraf E.K.; Parkes, Miles

doi:10.1002/ibd.22942

Cited by 139 publications

(126 citation statements)

References 29 publications

(35 reference statements)

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“…Studies have shown that DNA methylation is well correlated with various aspects of IBD, including disease duration and severity of inflammation (15,16). It is also known that the expression of histone deacetylase 3 (HDAC3), an epigenome-modifying enzyme, influences Significance TNFα is the key cytokine implicated in inflammatory bowel disease.…”

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confidence: 99%

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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confidence: 99%

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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“…Moreover, low concordance rates have been observed in monozygotic twin studies (3), leading to the hypothesis that epigenetic regulation also contributes to IBD pathogenesis. Changes in DNA and histone modifications associated with epigenetic regulation have been detected in IBD patients (3,4,9,11,12), but direct links to the IBD intestinal pathology have not been established. However, recent work has shown that IEC-specific deletion of the histone deacetylase HDAC3 results in increased susceptibility to intestinal damage and inflammation, although specific molecular targets remain to be identified (13).…”

mentioning

confidence: 99%

Epigenetic control of intestinal barrier function and inflammation in zebrafish

Marjoram¹,

Alvers²,

Deerhake

et al. 2015

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

162

164

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The intestinal epithelium forms a barrier protecting the organism from microbes and other proinflammatory stimuli. The integrity of this barrier and the proper response to infection requires precise regulation of powerful immune homing signals such as tumor necrosis factor (TNF). Dysregulation of TNF leads to inflammatory bowel diseases (IBD), but the mechanism controlling the expression of this potent cytokine and the events that trigger the onset of chronic inflammation are unknown. Here, we show that loss of function of the epigenetic regulator ubiquitin-like protein containing PHD and RING finger domains 1 (uhrf1) in zebrafish leads to a reduction in tnfa promoter methylation and the induction of tnfa expression in intestinal epithelial cells (IECs). The increase in IEC tnfa levels is microbe-dependent and results in IEC shedding and apoptosis, immune cell recruitment, and barrier dysfunction, consistent with chronic inflammation. Importantly, tnfa knockdown in uhrf1 mutants restores IEC morphology, reduces cell shedding, and improves barrier function. We propose that loss of epigenetic repression and TNF induction in the intestinal epithelium can lead to IBD onset.inflammation | Uhrf1 | DNA methylation | tumor necrosis factor | zebrafish I ntestinal epithelial cells (IECs) function as a barrier to prevent luminal contents from accessing underlying tissues, and loss of barrier function is a crucial factor leading to the development of inflammatory bowel diseases (IBD) (1). IBD, including Crohn's disease and ulcerative colitis, are intestinal disorders of poorly understood origin thought to arise from genetic susceptibility, luminal microbiota, immune responses, and environmental factors (2-4). A key element in IBD onset is the up-regulation of the proinflammatory cytokine tumor necrosis factor (TNF) by various cell types including immune cells and IECs. TNF overexpression has been detected in the Paneth cells within the epithelium of human IBD patients (5), and anti-TNF treatments are used successfully to treat patients with Crohn's disease (6). Previous research in mice has demonstrated that intestinal TNF exposure leads to loss of barrier function (7), and overexpression of TNF in mouse IECs is sufficient to elicit an IBD phenotype (8). Despite its pathogenic relevance, the genetic mechanisms regulating TNF expression and IBD onset remain largely unknown.Genome-wide association studies have identified numerous susceptibility loci associated with IBD including ubiquitin-like protein containing PHD and RING finger domains 1 (UHRF1) and the DNA methyltransferases DNMT1 and DNMT3a (9, 10), which are genes involved in DNA methylation controlling epigenetic transcriptional repression. Moreover, low concordance rates have been observed in monozygotic twin studies (3), leading to the hypothesis that epigenetic regulation also contributes to IBD pathogenesis. Changes in DNA and histone modifications associated with epigenetic regulation have been detected in IBD patients (3, 4, 9, 11, 12), but direct links to the I...

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“…Since epigenetic changes can also be detected in precancerous lesions tissues (Gonzalo et al, 2010) suggesting its potential role in the initial carcinogenesis (Petronis and Petroniene, 2000;Jawad, et al, 2011;Cooke, et al, 2012;Jenke and Zilbauer, 2012;Olaru, et al, 2012). Gene promoter hypermethylation in normal appearing colorectal mucosa has been suggested in the MGMT gene as well as, MLH1, TIMP3 and DAPK (Gonzalo, et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

“…The prevalence of gene silencing mediated by hypermethylation in IBD remains controversial, however considering the variable gene methylation prevalence reported in IBD-CRCs (Fleisher, et al, 2000;Konishi, et al, 2007;Dhir, et al, 2008;Cooke, et al, 2012;Olaru, et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

MGMT-B Gene Promoter Hypermethylation in Patients with Inflammatory Bowel Disease - A Novel Finding

Mokarram

Kavousipour²,

Sarabi³

et al. 2015

Asian Pacific Journal of Cancer Prevention

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Mucosal genome-wide methylation changes in inflammatory bowel disease

Abstract: Consistent differences in DNA methylation between IBD cases and controls at regulatory sites within these genes suggest that their altered transcription contributes to IBD pathogenesis.

Cited by 139 publications

References 29 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

Epigenetic control of intestinal barrier function and inflammation in zebrafish

MGMT-B Gene Promoter Hypermethylation in Patients with Inflammatory Bowel Disease - A Novel Finding

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