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.
authors.affiliation: Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Londoño Gentile
authors.forename: Chao
authors.initials: C
authors.lastname: Lu
authors.forename: Peter M
authors.initials: PM
authors.lastname: Lodato
authors.forename: Sarah
authors.initials: S
authors.lastname: Tse
authors.forename: Scott H
authors.initials: SH
authors.lastname: Olejniczak
authors.forename: Eric S
authors.initials: ES
authors.lastname: Witze
authors.forename: Craig B
authors.initials: CB
authors.lastname: Thompson
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Wellen
mesh_terms: D041721:3T3-L1 Cells; D001275:ATP Citrate (pro-S)-Lyase / Q000235:genetics* / Q000378:metabolism; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000235:genetics*; D002460:Cell Line; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D015870:Gene Expression; D057809:HEK293 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D008938:Mitosis / Q000235:genetics; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D006657:Histones; D035683:MicroRNAs; C554644:Mirn148 microRNA, mouse; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; C000619381:Dnmt1 protein, mouse; D001275:ATP Citrate (pro-S)-Lyase; D008239:Lysine
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