Coordinated regulation of microRNA genes in C19MC by SETDB1

Abstract

The microRNA (miRNA) gene cluster on chromosome 19, C19MC, is the largest primate-specific miRNA gene cluster. The 46 homologous miRNA genes in C19MC are highly expressed in the placenta, but repressed in other tissues by DNA methylation. Here, we found that the SET domain bifurcated 1(SETDB1), a histone H3-lysine 9 (H3K9)-specific methyltransferase 1, transcriptionally controls C19MC miRNA genes in a coordinated manner in human HAP1 cells. SETDB1 knockout (KO) resulted in the overexpression of C19MC miRNA genes, which was accompanied by a reduction of H3K9 trimethylation (H3K9me3) in the cluster. We found that SETDB1 specifically binds to and modifies the upstream promoter locus of C19MC with H3K9me3, suggesting its role as a C19MC repressor. Overexpression of C19MC miRNA genes was not related to DNA methylation because cytosine methylation levels were not altered in the C19MC of SETDB1 KO cells, indicating that SETDB1 KO does not cause DNA demethylation in the C19MC promoter and body regions. In conclusion, our results suggest that SETDB1 binding and H3K9 methylation at the C19MC promoter and body regions are responsible for the coordinated regulation of miRNA genes in the cluster.