Oxidative Damage Targets Complexes Containing DNA Methyltransferases, SIRT1, and Polycomb Members to Promoter CpG Islands

O’Hagan, Heather M.; Wang, Wei; Sen, Subhojit; Shields, Christina E. DeStefano; Lee, Stella S.; Zhang, Yang W.; Clements, Eriko G.; Cai, Yi; Neste, Leander Van; Easwaran, Hariharan; Casero, Robert A.; Sears, Cynthia L.; Baylin, Stephen B.

doi:10.1016/j.ccr.2011.09.012

Cited by 462 publications

(463 citation statements)

References 38 publications

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“…As a consequence, Sirt1-deficient HSPCs showed increased radiation sensitivity, p53 activation, and apoptosis and a decline in LT-HSC number and function after serial transplantation. These findings are in agreement with several recent studies demonstrating the detrimental impact of DNA formation of Sirt1-containing PcG complexes was enhanced in the presence of oxidative stress (O'Hagan et al, 2011); their physiological relevance, however, remained elusive. Our data now provide evidence that Sirt1 can directly modulate the expression of PcG target genes at the chromatin level, which may at least in part control maintenance of HSCs.…”

Section: Discussionsupporting

confidence: 82%

“…7, B and D). Increased H4K16-Ac was previously found to be inversely correlated with PcG-associated repressive marks (O'Hagan et al, 2011), and consistent with this notion, H3K27 trimethylation was reduced in the absence of Sirt1. Moreover, we observed a strikingly similar pattern of enrichment for both H3K27-me3 and Sirt1 across the Hoxa9 gene (Fig.…”

Section: Discussionsupporting

confidence: 69%

“…The closest mammalian Sir2 ortholog, Sirt1, is further involved in the transcriptional regulation of several key developmental regulators (Calvanese et al, 2010;Haigis and Sinclair, 2010;Lu et al, 2011) and was reported to associate with the stem cell-specific Polycomb group (PcG) repressive complex PRC4, preferentially under conditions of oxidative stress (Kuzmichev et al, 2005;O'Hagan et al, 2011). Consistent with a role for Sirt1 in stem cell homeostasis, Sirt1-deficient embryonic stem (ES) cells show increased sensitivity to oxidative stress, DNA damage accumulation, and genomic instability (Oberdoerffer et al, 2008; cues (Narala et al, 2008;Leko et al, 2012;Matsui et al, 2012;Peled et al, 2012).…”

mentioning

confidence: 82%

“…Notably, a modest increase in H4K16 acetylation was also observed at two neighboring Hox-A cluster genes, Hoxa10 (Cao and Zhang, 2004). Notably, Sirt1 was found in complex with several PcG components in an interaction that is enhanced in response to stress (Kuzmichev et al, 2005;O'Hagan et al, 2011). To investigate if Sirt1 regulates Hoxa9 at the chromatin level, we performed chromatin immunoprecipitation (ChIP) for Sirt1 in in vitro-expanded hematopoietic progenitor cells and found Sirt1 enrichment at the Hoxa9 locus, which was most pronounced in the gene body (Fig.…”

Section: Sirt1 Ablation Promotes Hyperproliferation and Increased Hoxmentioning

confidence: 93%

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Sirt1 ablation promotes stress-induced loss of epigenetic and genomic hematopoietic stem and progenitor cell maintenance

Singh¹,

Williams²,

Klarmann³

et al. 2013

J Cell Biol

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The (histone) deacetylase Sirt1 is a mediator of genomic and epigenetic maintenance, both of which are critical aspects of stem cell homeostasis and tightly linked to their functional decline in aging and disease. We show that Sirt1 ablation in adult hematopoietic stem and progenitor cells (HSPCs) promotes aberrant HSPC expansion specifically under conditions of hematopoietic stress, which is associated with genomic instability as well as the accumulation of DNA damage and eventually results in a loss of long-term progenitors. We further demonstrate that progenitor cell expansion is mechanistically linked to the selective upregulation of the HSPC maintenance factor and polycomb target gene Hoxa9. We show that Sirt1 binds to the Hoxa9 gene, counteracts acetylation of its histone target H4 lysine 16, and in turn promotes polycomb-specific repressive histone modification. Together, these findings demonstrate a dual role for Sirt1 in HSPC homeostasis, both via epigenetic regulation of a key developmental gene and by promoting genome stability in adult stem cells.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionsupporting

confidence: 69%

mentioning

confidence: 82%

Section: Sirt1 Ablation Promotes Hyperproliferation and Increased Hoxmentioning

confidence: 93%

See 2 more Smart Citations

Sirt1 ablation promotes stress-induced loss of epigenetic and genomic hematopoietic stem and progenitor cell maintenance

Singh¹,

Williams²,

Klarmann³

et al. 2013

J Cell Biol

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“…2 μM ruxolitinib (Invivogen #tlrl-rux), 0.625-5 U/mL of anti-IFNAR2 antibody (PBL Interferon Source #21385-1), 0.625-2.5 U/mL of anti-IFNB antibody (PBL Interferon Source #31400-1), or 1.25-5 U/mL of anti-IL10RB antibody (Abcam # ab89884) were added during DNMTi treatment. Preparation of nuclear and cytoplasmic fractions of cultured cells was performed as described (O'Hagan et al, 2011). Ribosomal RNA was depleted using the Ribominus kit (Invitrogen), and PolyA+ and PolyA− RNA were isolated using the Oligotex Direct mRNA Mini Kit (Invitrogen).…”

Section: Discussionmentioning

confidence: 99%

Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses

Chiappinelli¹,

Strissel²,

Desrichard³

et al. 2017

Cell

103

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SummaryWe show that DNA methyltransferase inhibitors (DNMTis) upregulate immune signaling in cancer through the viral defense pathway. In ovarian cancer (OC), DNMTis trigger cytosolic sensing of double-stranded RNA (dsRNA) causing a Type I Interferon response and apoptosis. Knocking down dsRNA sensors TLR3 and MAVS reduces this response twofold, and blocking interferon beta or its receptor abrogates it. Upregulation of hypermethylated endogenous retrovirus (ERV) genes accompanies the response and ERV overexpression activates the response. Basal levels of ERV and viral defense gene expression significantly correlate in primary OC and the latter signature separates primary samples for multiple tumor types from The Cancer Genome Correspondence should be addressed to Reiner.Strick@uk-erlangen.de and sbaylin@jhmi.edu.. 7 Co-first authors. 8 Co-senior authors.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.Author Contributions KBC, PLS, AD, TM, JW, TAC, SBB, and RS designed experiments, performed data analyses, and wrote the manuscript. KBC, PLS, CH, AD, AH, BA, and SB performed experiments. NSR provided ERV-3 env cDNA plasmid and DS provided ovarian cancer cell lines. HL, AS, VM, DMP, LMC, MWB, and CAZ assisted with data analyses. TM, TAC, SBB, and RS contributed equally to this work and are co-senior authors. HHS Public Access

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The study of expression levels of DNA methylation regulators in patients affected with congenital heart defects (CHDs)

Joshi¹,

Kukshal²,

Chellappan³

et al. 2022

Birth Defects Research

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Background: Congenial heart defects (CHDs) have multifactorial etiology with complex interplay of genetic and environmental factors. Environmental impact can have epigenetic mechanism of CHD development. Many studies have reported the causal association between CHD and distinct DNA methylation profile which is one of the key epigenetic events, which has vital role in normal embryonic development. The products of DNMT1, DNMT3A, DNMT3B, and MBD2 are important regulators of DNA methylation process.Changes in the expression of these genes are implicated in congenital structural cardiac defects. Hence, in this proof-of-concept study, we have compared the expression levels of these genes in the blood samples of healthy controls and CHD cases while investigating the etiology of CHD. Methods: In this study with 48 CHD cases and 47 healthy controls, total RNA was isolated from the whole blood samples using TRI reagent. Quantitative RT PCR (qRT-PCR) was used to analyze the mRNA levels of DNMT1, DNMT3A, DNMT3B, and MBD2. The expression levels have been analyzed by relative quantification. Results: We observed that DNMT3B (fold change = À2.563; p = .0018) and DNMT3A (fold change = À2.169; p = .05) were significantly downregulated in CHD patients, whereas the expression of DNMT1 and MBD2 was not significantly different between cases and controls.Conclusions: Lower expression of de novo methyltransferases, namely, DNMT3B and DNMT3A in CHD cases, may be an important contributor to the mechanism of CHD pathogenesis. Further studies with age-matched controls and analysis of global DNA methylation profile are required to investigate the proposed causal association.

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Oxidative Damage Targets Complexes Containing DNA Methyltransferases, SIRT1, and Polycomb Members to Promoter CpG Islands

Cited by 462 publications

References 38 publications

Sirt1 ablation promotes stress-induced loss of epigenetic and genomic hematopoietic stem and progenitor cell maintenance

Sirt1 ablation promotes stress-induced loss of epigenetic and genomic hematopoietic stem and progenitor cell maintenance

Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses

The study of expression levels of DNA methylation regulators in patients affected with congenital heart defects (CHDs)

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