| Article ID | Journal | Published Year | Pages | File Type |
|---|---|---|---|---|
| 2039168 | Cell Reports | 2015 | 9 Pages |
•Deleting Hdac1/2 in oocytes results in a global decrease in DNA methylation•Deleting Hdac1/2 in oocytes results in failure to establish imprinting marks•Double mutants show increased retrotransposon expression and DNA double-strand breaks•HDAC2 and DNMT3A2 reside in a complex essential for genomic imprinting
SummaryMaternal 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.
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