UHRF1 phosphorylation by cyclin A2/cyclin-dependent kinase 2 is required for zebrafish embryogenesis

Chu, Jaime; Loughlin, Elizabeth A.; Gaur, Naseem A.; SenBanerjee, Sucharita; Jacob, Vinitha; Monson, Christopher; Kent, Brandon; Oranu, Amanke; Ding, Yuanying; Ukomadu, Chinweike; Sadler, Kirsten C.

doi:10.1091/mbc.e11-06-0487

Cited by 45 publications

(67 citation statements)

References 70 publications

(139 reference statements)

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“…To determine whether this acute cell cycle block in uhrf1 mutants contributed to the uhrf1 mutant phenotype at 120 hpf, we used a heat-shock inducible transgene [Tg(hsp70l:UHRF1-GFP) (Chu et al, 2012)] to replace UHRF1 expression transiently in the embryo at 24, 32, 54 and 72 hpf, and then assessed larvae at 120 hpf for overall (Fig. 4C) and hepatic (Fig.…”

Section: Cell Cycle Arrest Results In Apoptosismentioning

confidence: 99%

“…We next asked whether Uhrf1 was required in a cell-autonomous fashion during hepatic outgrowth by crossing uhrf1 mutants to a transgenic line expressing low levels of UHRF1-GFP exclusively in hepatocytes [Tg(fabp10:UHRF1-GFP) LOW , hereafter referred to as UHRF1-GFP Low] (Chu et al, 2012;Mudbhary et al, 2014). The non-hepatic phenotypes were not altered in uhrf1 mutants expressing UHRF1-GFP Low in hepatocytes (Fig.…”

Section: Cell Cycle Arrest Results In Apoptosismentioning

confidence: 99%

“…Zebrafish uhrf1 mutants survive to later developmental stages than mouse embryos because maternal supplies support early development (Chu et al, 2012). Mutant embryos display defects in multiple tissues, including the liver and eye (Sadler et al, 2007;Tittle et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Cell Cycle Arrest Results In Apoptosismentioning

confidence: 99%

Section: Cell Cycle Arrest Results In Apoptosismentioning

confidence: 99%

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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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“…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.

170

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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“…Ubiquitin-like with plant homeodomain (PHD) and RING finger domain 1 (UHRF1) is a multi-domain protein, which was initially identified as a nuclear protein associated with cell proliferation (4). As a human inverted CCAAT box-binding protein, UHRF1 is involved in regulating the expression of topoisomerase IIα in proliferating cells (5).…”

Section: Introductionmentioning

confidence: 99%

UHRF1 promotes human osteosarcoma cell invasion by downregulating the expression of E-cadherin in an Rb1-dependent manner

Liu

Qiao

Wang

et al. 2015

Molecular Medicine Reports

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Abstract. Ubiquitin-like with plant homeodomain (PHD) and RING-finger domain 1 (UHRF1) maintains methylation patterns following DNA replication and is expressed at high levels in various types of human cancer. UHRF1 has been identified as a novel oncogene involved in the pathogenesis of hepatocellular carcinoma. Previous studies have demonstrated that inhibition of the expression of UHRF1 suppresses the proliferation of cancer cells. However, the role of UHRF1 in human osteosarcoma has not been investigated. The present study examined the expression levels of UHRF1 and retinoblastoma 1 (Rb1) in human osteosarcoma cell lines by western blot analysis. Stable overexpression of UHRF1 or knockdown of Rb1 was achieved by lentiviral transfection. Subsequently, a Cell Counting Kit-8 assay and a cell invasion assay were performed to detect the biological functions of UHRF1 in vitro. The results of the present study demonstrated that UHRF1 promoted the proliferation of human osteosarcoma cells. The present study also reported that UHRF1 was able to enhance the invasion of osteosarcoma cells in a retinoblastoma 1 (Rb1)-dependent manner. UHRF1 promoted invasion in Rb1-positive osteosarcoma cells, but not in Saos-2 cells with homozygous loss of Rb1. Similarly, knockdown of Rb1 in Rb1-positive osteosarcoma cells enhanced levels of invasion and eliminated the regulation of invasion by UHRF1. UHRF1 was found to inhibit the mRNA and protein expression levels of Rb1. Furthermore, deletion of Rb1 was found to suppress the expression of E-cadherin and promote epithelial-to-mesenchymal transition (EMT). In addition, the overexpression of UHRF1 inhibited the expression of E-cadherin and promoted EMT via the suppression of Rb1. These data demonstrated that UHRF1 promotes osteosarcoma cell invasion by downregulating the expression of E-cadherin and increasing EMT in an Rb1-dependent manner.

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UHRF1 phosphorylation by cyclin A2/cyclin-dependent kinase 2 is required for zebrafish embryogenesis

Cited by 45 publications

References 70 publications

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

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

Epigenetic control of intestinal barrier function and inflammation in zebrafish

UHRF1 promotes human osteosarcoma cell invasion by downregulating the expression of E-cadherin in an Rb1-dependent manner

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