DNMT1 represses <i>p53</i> to maintain progenitor cell survival during pancreatic organogenesis

Georgia, Senta; Kanji, Murtaza; Bhushan, Anil

doi:10.1101/gad.207001.112

Cited by 69 publications

(80 citation statements)

References 33 publications

(30 reference statements)

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“…Our previous work has shown that DNA methylation is an important regulatory mechanism in pancreatic organogenesis during embryonic development, as well as in the specification and maintenance of β cell fate (49)(50)(51). In this manuscript, we show that de novo DNA methylation directs metabolic reprogramming of pancreatic β cells toward their functional maturation, and pancreatic β cells lacking DNA methyltransferase Dnmt3a metabolically and physiologically resemble functionally immature neonatal β cells.…”

Section: Discussionmentioning

confidence: 68%

DNA methylation directs functional maturation of pancreatic β cells

et al. 2015

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Section: Discussionmentioning

confidence: 68%

DNA methylation directs functional maturation of pancreatic β cells

et al. 2015

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“…Thus, we hypothesize that as the neonatal Dnmt1-ablated cells divide their DNA methylation levels are rapidly reduced, and Dnmt3a and Dnmt3b do not compensate for this loss. The high rate of proliferation in the neonatal intestine also distinguishes these findings concerning the developing intestine from studies of neuroblasts (Fan et al, 2001) or embryonic pancreas (Georgia et al, 2013).…”

Section: Discussionmentioning

confidence: 93%

“…In the fetal pancreas, deletion of Dnmt1 causes a decrease in differentiated pancreatic cells with a concomitant increase in p53 levels, cell cycle arrest and progenitor cell apoptosis. However, this phenotype is dependent on direct binding of the Dnmt1 protein to the p53 (Trp53) locus, and was suggested to be caused by a DNA methylation-independent effect of Dnmt1 (Georgia et al, 2013). Thus, it remains unclear whether and how Dnmt1 and maintenance DNA methylation control different organs during development.…”

Section: Introductionmentioning

confidence: 99%

Dnmt1 is essential to maintain progenitors in the perinatal intestinal epithelium

et al. 2015

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The DNA methyltransferase Dnmt1 maintains DNA methylation patterns and genomic stability in several in vitro cell systems. Ablation of Dnmt1 in mouse embryos causes death at the postgastrulation stage; however, the functions of Dnmt1 and DNA methylation in organogenesis remain unclear. Here, we report that Dnmt1 is crucial during perinatal intestinal development. Loss of Dnmt1 in intervillus progenitor cells causes global hypomethylation, DNA damage, premature differentiation, apoptosis and, consequently, loss of nascent villi. We further confirm the crucial role of Dnmt1 during crypt development using the in vitro organoid culture system, and illustrate a clear differential requirement for Dnmt1 in immature versus mature organoids. These results demonstrate an essential role for Dnmt1 in maintaining genomic stability during intestinal development and the establishment of intestinal crypts.

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“…A primary role of Uhrf1 is to recruit DNMT1 to replicating DNA where it acts to maintain methylation patterns at CpG dinucleotides through replication (28)(29)(30)(31)(32). In vertebrates, promoters with low CpG density acquire DNA methylation during development (33), which has been correlated with repression of transcriptional activity (34) and demonstrated to cause promoter silencing (35).…”

Section: Resultsmentioning

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.

163

166

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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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DNMT1 represses p53 to maintain progenitor cell survival during pancreatic organogenesis

Cited by 69 publications

References 33 publications

DNA methylation directs functional maturation of pancreatic β cells

DNA methylation directs functional maturation of pancreatic β cells

Dnmt1 is essential to maintain progenitors in the perinatal intestinal epithelium

Epigenetic control of intestinal barrier function and inflammation in zebrafish

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