Abstract
We have examined the role of Fam60a, a gene highly expressed in embryonic stem cells, in mouse development. Fam60a interacts with components of the Sin3a-Hdac transcriptional corepressor complex, and most Fam60a-/- embryos manifest hypoplasia of visceral organs and die in utero. Fam60a is recruited to the promoter regions of a subset of genes, with the expression of these genes being either up- or down-regulated in Fam60a-/- embryos. The DNA methylation level of the Fam60a target gene Adhfe1 is maintained at embryonic day (E) 7.5 but markedly reduced at E9.5 in Fam60a-/- embryos, suggesting that DNA demethylation is enhanced in the mutant. Examination of genome-wide DNA methylation identified several differentially methylated regions, which were preferentially hypomethylated, in Fam60a-/- embryos. Our data suggest that Fam60a is required for proper embryogenesis, at least in part as a result of its regulation of DNA methylation at specific gene promoters.
Highlights
The Sin3a protein is a core component of a mammalian transcriptional corepressor complex that includes histone deacetylases (Hdacs) (Hassig et al, 1997; Zhang et al, 1997)
Further co-immunoprecipitation analysis confirmed that Fam60a interacts with components of the Sin3a-Hdac complex
Reciprocal co-immunoprecipitation analysis with nuclear extracts of E10.5 WT embryos revealed that Fam60a was present in immunoprecipitates prepared with antibodies to Sin3a or to Hdac1 but not in those prepared with antibodies to Hdac2 (Figure 1B), suggesting that the association between Hdac2 and Fam60a is relatively weak
Summary
The Sin3a protein is a core component of a mammalian transcriptional corepressor complex that includes histone deacetylases (Hdacs) (Hassig et al, 1997; Zhang et al, 1997). Mice lacking Sin3a die during embryogenesis around the time of implantation (McDonel et al, 2012), suggesting that the Sin3a-Hdac complex is essential for early embryonic development. This complex was initially thought only to repress gene expression, it can stimulate transcription in a manner dependent on cellular context (Icardi et al, 2012). DNA methylation occurs predominantly at CpG sequences, with ~70% of gene promoters in mammalian genomes containing CpG islands. The methylation pattern of genomic DNA is established at the peri-implantation stage
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