Uhrf1-dependent H3K23 ubiquitylation couples maintenance DNA methylation and replication

Nishiyama, Atsuya; Yamaguchi, Luna; Sharif, Jafar; Johmura, Yoshikazu; Kawamura, Takeshi; Nakanishi, Kazuyoshi; Shimamura, Shintaro; Arita, Kyohei; Kodama, Tatsuhiko; Ishikawa, Fuyuki; Koseki, Haruhiko; Nakanishi, Makoto

doi:10.1038/nature12488

Cited by 344 publications

(416 citation statements)

References 34 publications

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“…Our study unravels unexpected interactions between LMO2 and three essential replication proteins, MCM6, PRIM1, and POLD1 (30), as well as chromatin-modifying enzymes that have wellcharacterized roles in DNA replication, BAZ1A, SETD8, MYST2, and UHRF1 (31)(32)(33)47). More importantly, tethering LMO2 to DNA via the GAL4-DNA binding domain was sufficient to recruit MCM5 and POLD1 to DNA and to transform UAS into origins of replication, indicating that LMO2 directly controls DNA replication.…”

Section: Discussionmentioning

confidence: 67%

The LMO2 oncogene regulates DNA replication in hematopoietic cells

Sincennes

Humbert

Grondin

et al. 2016

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

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Oncogenic transcription factors are commonly activated in acute leukemias and subvert normal gene expression networks to reprogram hematopoietic progenitors into preleukemic stem cells, as exemplified by LIM-only 2 (LMO2) in T-cell acute lymphoblastic leukemia (T-ALL). Whether or not these oncoproteins interfere with other DNA-dependent processes is largely unexplored. Here, we show that LMO2 is recruited to DNA replication origins by interaction with three essential replication enzymes: DNA polymerase delta (POLD1), DNA primase (PRIM1), and minichromosome 6 (MCM6). Furthermore, tethering LMO2 to synthetic DNA sequences is sufficient to transform these sequences into origins of replication. We next addressed the importance of LMO2 in erythroid and thymocyte development, two lineages in which cell cycle and differentiation are tightly coordinated. Lowering LMO2 levels in erythroid progenitors delays G1-S progression and arrests erythropoietin-dependent cell growth while favoring terminal differentiation. Conversely, ectopic expression in thymocytes induces DNA replication and drives these cells into cell cycle, causing differentiation blockade. Our results define a novel role for LMO2 in directly promoting DNA synthesis and G1-S progression.M ore than 70% of recurring chromosomal translocations in T-cell acute lymphoblastic leukemia (T-ALL) involve transcription factors that are master regulators of cell fate. These oncogenic transcription factors determine the gene signature and leukemic cell types (1). Whether these DNA-bound factors may have additional roles beyond modulating gene expression remains unknown. LMO2, a 17-kDa protein defined by tandem zinc finger domains, is an essential nucleation factor that assembles a multipartite transcriptional regulatory complex on gene regulatory regions via direct interaction with the TAL1/SCL transcription factor, LDB1, and other DNA binding transcription factors (2-4, reviewed in refs. 5, 6). These complexes drive gene expression programs that determine hematopoietic cell fates at critical branchpoints both during embryonic development (7) and in adult hematopoietic stem cells (8, 9). Lmo2 function is essential in highly proliferative erythroid progenitors (10, reviewed in refs. 5, 6). Interestingly, Lmo2 down-regulation is required for terminal erythroid differentiation (11,12). Because commitment to terminal differentiation is coordinated with growth arrest (13), Lmo2 may have additional molecular functions that impede this critical step marked by growth cessation.In mouse models of T-ALL, LMO1 or LMO2 collaborates with SCL to inhibit the activity of two basic helix-loop-helix (bHLH) transcription factors that control thymocyte differentiation, E2A/ TCF3 and HEB/TCF12, causing differentiation arrest (reviewed in ref. 14). However, this inhibition is not sufficient, per se, for leukemogenesis, because both TAL1 and LYL1 inhibit E proteins but require interaction with LMO1/2 to activate the transcription of a self-renewal gene network in thymocytes (15,16) and to induc...

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Section: Discussionmentioning

confidence: 67%

The LMO2 oncogene regulates DNA replication in hematopoietic cells

Sincennes

Humbert

Grondin

et al. 2016

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

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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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“…The SRA (SET and RING fingerassociated) domain of Uhrf1 specifically recognizes hemimethylated CpG and flips the methylated cytosines out of double-stranded DNA (17)(18)(19). Recently, it was reported that Dnmt1 recognizes ubiquitylated lysine 23 of histone H3, which is catalyzed by the RING finger E3 ligase activity of Uhrf1 and is a necessary step for maintenance methylation (20).…”

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confidence: 99%

The DNA Methyltransferase Dnmt1 Directly Interacts with the SET and RING Finger-associated (SRA) Domain of the Multifunctional Protein Uhrf1 to Facilitate Accession of the Catalytic Center to Hemi-methylated DNA

Berkyurek

Suetake

Arita

et al. 2014

Journal of Biological Chemistry

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112

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Background: Dnmt1 faithfully propagates DNA methylation patterns to the next generation. Results: The DNA methylation activity of Dnmt1 was stimulated by the direct interaction of the SRA domain of Uhrf1 and Dnmt1. Conclusion:The SRA facilitates DNA accession to the catalytic center. Significance: The RFTS and SRA interaction contributes to the correct feeding of the hemi-methylated DNA to the catalytic center of Dnmt1.

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Uhrf1-dependent H3K23 ubiquitylation couples maintenance DNA methylation and replication

Cited by 344 publications

References 34 publications

The LMO2 oncogene regulates DNA replication in hematopoietic cells

The LMO2 oncogene regulates DNA replication in hematopoietic cells

Epigenetic control of intestinal barrier function and inflammation in zebrafish

The DNA Methyltransferase Dnmt1 Directly Interacts with the SET and RING Finger-associated (SRA) Domain of the Multifunctional Protein Uhrf1 to Facilitate Accession of the Catalytic Center to Hemi-methylated DNA

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