The epigenetic regulator Uhrf1 facilitates the proliferation and maturation of colonic regulatory T cells

Obata, Yuichi; Furusawa, Yukihiro; Endo, Takaho A.; Sharif, Jafar; Takahashi, Daisuke; Atarashi, Koji; Nakayama, Manabu; Onawa, Satoshi; Fujimura, Y; Takahashi, Mayuko; Ikawa, Tomokatsu; Otsubo, Takeshi; Kawamura, Yuki I.; Dohi, Taeko; Tsuji, Shoji; Masumoto, Hiroshi; Ohara, Osamu; Honda, Kenya; Hori, Shohei; Ohno, Hiroshi; Koseki, Haruhiko; Hase, Koji

doi:10.1038/ni.2886

Cited by 160 publications

(153 citation statements)

References 48 publications

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“…Importantly, genome-wide association studies of Crohn's disease and ulcerative colitis patients have identified SNPs near UHRF1, DNMT1, and DNMT3a (37,38), suggesting that alterations in these genes may lead to IBD. Although alternative roles for UHRF1 including cell cycle regulation and histone ubiquitylation have been identified (39)(40)(41), up-regulation of tnfa in the intestine of both uhrf1 pd1092 and dnmt1 pd1093 mutants strongly suggests that it is the loss of DNA methylation at CpG dinucleotides at the tnfa promoter that leads to elevated tnfa expression.…”

Section: Discussionmentioning

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.

167

168

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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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Section: Discussionmentioning

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.

167

168

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“…Commensal bacteriaderived signals also influence host epigenetic pathways, particularly through DNA and histone methylation [32][33][34][35][36] and histone acetylation and deacetylation [37][38][39][40][41] . The commensal microbiota produces multiple low-molecular-weight byproducts that modify the host cell epigenome and may alter the functional behavior of host cells.…”

Section: Special Issue (Mini Review) Gut Microbiota and Epigeneticsmentioning

confidence: 99%

Commensal microbiota-derived signals regulate host immune system through epigenetic modifications

Takahashi

Hase

2015

Inflammation and Regeneration

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Commensal microbiota colonizing the digestive tract is a symbiotic partner of its host, as it plays a critical role in nutrient metabolism as well as the development and maturation of the host immune system. Although it is clear that regulation of the host-commensal relationship is crucial to mammalian health, the underlying mechanisms regulating gut homeostasis are yet to be elucidated. Epigenetic modifications, including DNA methylation and histone methylation/acetylation, alter the structure of chromatin to regulate the transcriptional program of eukaryotic cells. At the whole genome level, these modifications possibly play a key role in regulating the mutually beneficial relationship between the host and the gut microbiota. In this review, we describe how the commensal microbiota and its metabolic by-products modify the epigenome of host cells, and in turn, change their development and functional behavior.Rec.2/24/2015, Acc.3/1/2015, pp129-136

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“…Therefore, it is assumed that the cellular phenotypes resulting from altering epigenetic modifiers are attributed to direct changes in the expression of genes that are under epigenetic control. For example, Uhrf1-deficient mouse T-cells have increased Cdkna1 expression that is associated with reduced methylation in its promoter (Obata et al, 2014), and this epigenetic derepression could account for its upregulation. An alternative hypothesis is that a surveillance mechanism for epigenetic damage elicits a cellular response to prevent propagation of cells with epigenetic damage, analogous to the DNA damage response (Milutinovic et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

DNA hypomethylation induces a DNA replication-associated cell cycle arrest to block hepatic outgrowth in uhrf1 mutant zebrafish embryos

et al. 2015

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UHRF1 (ubiquitin-like, containing PHD and RING finger domains, 1) recruits DNMT1 to hemimethylated DNA during replication and is essential for maintaining DNA methylation. uhrf1 mutant zebrafish have global DNA hypomethylation and display embryonic defects, including a small liver, and they die as larvae. We make the surprising finding that, despite their reduced organ size, uhrf1 mutants express high levels of genes controlling S-phase and have many more cells undergoing DNA replication, as measured by BrdU incorporation. In contrast to wild-type hepatocytes, which are continually dividing during hepatic outgrowth and thus dilute the BrdU label, uhrf1 mutant hepatocytes retain BrdU throughout outgrowth, reflecting cell cycle arrest. Pulse-chase-pulse experiments with BrdU and EdU, and DNA content analysis indicate that uhrf1 mutant cells undergo DNA re-replication and that apoptosis is the fate of many of the rereplicating and arrested hepatocytes. Importantly, the DNA rereplication phenotype and hepatic outgrowth failure are preceded by global loss of DNA methylation. Moreover, uhrf1 mutants are phenocopied by mutation of dnmt1, and Dnmt1 knockdown in uhrf1 mutants enhances their small liver phenotype. Together, these data indicate that unscheduled DNA replication and failed cell cycle progression leading to apoptosis are the mechanisms by which DNA hypomethylation prevents organ expansion in uhrf1 mutants. We propose that cell cycle arrest leading to apoptosis is a strategy that restricts propagation of epigenetically damaged cells during embryogenesis.

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The epigenetic regulator Uhrf1 facilitates the proliferation and maturation of colonic regulatory T cells

Cited by 160 publications

References 48 publications

Epigenetic control of intestinal barrier function and inflammation in zebrafish

Epigenetic control of intestinal barrier function and inflammation in zebrafish

Commensal microbiota-derived signals regulate host immune system through epigenetic modifications

DNA hypomethylation induces a DNA replication-associated cell cycle arrest to block hepatic outgrowth in uhrf1 mutant zebrafish embryos

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