DNMT1 Is regulated by ATP-citrate lyase and maintains methylation patterns during adipocyte differentiation Journal Article

   

Authors:	Gentile, T. L.; Lu, C.; Lodato, P. M.; Tse, S.; Olejniczak, S. H.; Witze, E. S.; Thompson, C. B.; Wellen, K. E.
Article Title:	DNMT1 Is regulated by ATP-citrate lyase and maintains methylation patterns during adipocyte differentiation
Abstract:	During adipocyte differentiation, significant epigenomic changes occur in association with the implementation of the adipogenic program. We have previously shown that histone acetylation increases during differentiation in a manner dependent on acetyl coenzyme A (acetyl-CoA) production by the enzyme ATP-citrate lyase (ACL). Whether ACL regulates nuclear targets in addition to histones during differentiation is not clear. In this study, we report that DNA methyltransferase 1 (DNMT1) levels in adipocytes are controlled in part by ACL and that silencing of DNMT1 can accelerate adipocyte differentiation. DNMT1 gene expression is induced early in 3T3-L1 adipocyte differentiation during mitotic clonal expansion and is critical for maintenance of DNA and histone H3K9 methylation patterns during this period. In the absence of DNMT1, adipocyte-specific gene expression and lipid accumulation occur precociously. Later in differentiation, DNMT1 levels decline in an ACL-dependent manner. ACL-mediated suppression of DNMT1 occurs at least in part by promoting expression of microRNA 148a (miR-148a), which represses DNMT1. Ectopic expression of miR-148a accelerates differentiation under standard conditions and can partially rescue a hypermethylation-mediated differentiation block. The data suggest a role for DNMT1 in modulating the timing of differentiation and describe a novel ACL-miR-148a-dependent mechanism for regulating DNMT1 during adipogenesis. © 2013, American Society for Microbiology.
Keywords:	controlled study; nonhuman; polymerase chain reaction; animal cell; mouse; microrna; gene expression; lipid; small interfering rna; dexamethasone; cell differentiation; enzyme activity; dna methylation; cell specificity; dna; chromatin immunoprecipitation; histone h3; immunoblotting; insulin; gene silencing; metabolite; cell strain 3t3; dna methyltransferase 1; complementary dna; acetylation; adipocyte; white adipose tissue; carbon 14; deoxyglucose; troglitazone; adenosine triphosphate citrate lyase; isobutylmethylxanthine
Journal Title:	Molecular and Cellular Biology
Volume:	33
Issue:	19
ISSN:	0270-7306
Publisher:	American Society for Microbiology
Date Published:	2013-10-01
Start Page:	3864
End Page:	3878
Language:	English
DOI:	10.1128/mcb.01495-12
PROVIDER:	scopus
PMCID:	PMC3811875
PUBMED:	23897429
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-84886768058&partnerID=40&md5=397d9882bfc934ab4cbce40cdd1fff82
Notes:	--- - "Export Date: 2 December 2013" - "CODEN: MCEBD" - "Source: Scopus"

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