Development and Differentiation Research Center, Aging Convergence Research Center (ACRC), Korea Research Institute of Bioscience Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, South Korea; Department of Functional Genomics, Korea University of Science and Technology (UST), 217 Gajeong-ro, Yuseong-gu, Daejeon, 34113, South Korea.
Development and Differentiation Research Center, Aging Convergence Research Center (ACRC), Korea Research Institute of Bioscience Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, South Korea.
Biochem Biophys Res Commun. 2022 Dec 31;637:17-22. doi: 10.1016/j.bbrc.2022.11.004. Epub 2022 Nov 5.
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.
19 号染色体上的 microRNA（miRNA）基因簇 C19MC 是最大的灵长类特异性 miRNA 基因簇。C19MC 中的 46 个同源 miRNA 基因在胎盘组织中高表达，但通过 DNA 甲基化在其他组织中受到抑制。在这里，我们发现 SET 域二分体 1（SETDB1），一种组蛋白 H3-赖氨酸 9（H3K9）特异性甲基转移酶 1，在人 HAP1 细胞中以协调的方式转录控制 C19MC miRNA 基因。SETDB1 敲除（KO）导致 C19MC miRNA 基因的过表达，同时伴随着簇中 H3K9 三甲基化（H3K9me3）的减少。我们发现 SETDB1 特异性结合并修饰 C19MC 的上游启动子位点，并用 H3K9me3 进行修饰，表明其作为 C19MC 抑制剂的作用。C19MC miRNA 基因的过表达与 DNA 甲基化无关，因为 SETDB1 KO 细胞中 C19MC 的胞嘧啶甲基化水平没有改变，这表明 SETDB1 KO 不会导致 C19MC 启动子和主体区域的 DNA 去甲基化。总之，我们的结果表明，SETDB1 在 C19MC 启动子和主体区域的结合和 H3K9 甲基化负责协调该簇中 miRNA 基因的表达。
