title: A DNMT3A2-HDAC2 Complex Is Essential for Genomic Imprinting and Genome Integrity in Mouse Oocytes.
abstract: Maternal genomic imprints are established during oogenesis. Histone deacetylases (HDACs) 1 and 2 are required for oocyte development in mouse, but their role in genomic imprinting is unknown. We find that Hdac1:Hdac2(-/-) double-mutant growing oocytes exhibit global DNA hypomethylation and fail to establish imprinting marks for Igf2r, Peg3, and Srnpn. Global hypomethylation correlates with increased retrotransposon expression and double-strand DNA breaks. Nuclear-associated DNMT3A2 is reduced in double-mutant oocytes, and injecting these oocytes with Hdac2 partially restores DNMT3A2 nuclear staining. DNMT3A2 co-immunoprecipitates with HDAC2 in mouse embryonic stem cells. Partial loss of nuclear DNMT3A2 and HDAC2 occurs in Sin3a(-/-) oocytes, which exhibit decreased DNA methylation of imprinting control regions for Igf2r and Srnpn, but not Peg3. These results suggest seminal roles of HDAC1/2 in establishing maternal genomic imprints and maintaining genomic integrity in oocytes mediated in part through a SIN3A complex that interacts with DNMT3A2.
authors.affiliation: Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Pengpeng
authors.initials: P
authors.lastname: Ma
authors.affiliation: Department of Cell and Developmental Biology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: de Waal
authors.affiliation: Department of Cell and Developmental Biology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Jamie R
authors.initials: JR
authors.lastname: Weaver
authors.affiliation: Department of Cell and Developmental Biology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Marisa S
authors.initials: MS
authors.lastname: Bartolomei
authors.affiliation: Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: rschultz@sas.upenn.edu.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Schultz
mesh_terms: D000818:Animals; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D053903:DNA Breaks, Double-Stranded; D019175:DNA Methylation / Q000235:genetics; D000090205:DNA Methyltransferase 3A; D053595:Embryonic Stem Cells / Q000502:physiology; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D016678:Genome / Q000235:genetics*; D018392:Genomic Imprinting / Q000235:genetics*; D056284:Histone Deacetylase 1 / Q000235:genetics; D056464:Histone Deacetylase 2 / Q000235:genetics*; D051379:Mice; D009865:Oocytes / Q000502:physiology*; D009866:Oogenesis / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D056264:Sin3 Histone Deacetylase and Corepressor Complex
chemical_list: D012097:Repressor Proteins; C099683:SIN3A transcription factor; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; C533424:Hdac2 protein, mouse; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D056264:Sin3 Histone Deacetylase and Corepressor Complex