Department of Medical Genetics, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada.
Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences (IMS), Yokohama, Kanagawa, Japan.
Nat Commun. 2021 Dec 2;12(1):7020. doi: 10.1038/s41467-021-27345-x.
Silencing of a subset of germline genes is dependent upon DNA methylation (DNAme) post-implantation. However, these genes are generally hypomethylated in the blastocyst, implicating alternative repressive pathways before implantation. Indeed, in embryonic stem cells (ESCs), an overlapping set of genes, including germline "genome-defence" (GGD) genes, are upregulated following deletion of the H3K9 methyltransferase SETDB1 or subunits of the non-canonical PRC1 complex PRC1.6. Here, we show that in pre-implantation embryos and naïve ESCs (nESCs), hypomethylated promoters of germline genes bound by the PRC1.6 DNA-binding subunits MGA/MAX/E2F6 are enriched for RING1B-dependent H2AK119ub1 and H3K9me3. Accordingly, repression of these genes in nESCs shows a greater dependence on PRC1.6 than DNAme. In contrast, GGD genes are hypermethylated in epiblast-like cells (EpiLCs) and their silencing is dependent upon SETDB1, PRC1.6/RING1B and DNAme, with H3K9me3 and DNAme establishment dependent upon MGA binding. Thus, GGD genes are initially repressed by PRC1.6, with DNAme subsequently engaged in post-implantation embryos.
生殖系基因的一部分沉默依赖于植入后的 DNA 甲基化 (DNAme)。然而，这些基因在囊胚中通常是低甲基化的，这表明在植入前存在替代的抑制途径。事实上，在胚胎干细胞 (ESCs) 中，一组重叠的基因，包括生殖系“基因组防御”(GGD)基因，在 H3K9 甲基转移酶 SETDB1 或非典型 PRC1 复合物 PRC1.6 的亚基缺失后被上调。在这里，我们表明在植入前胚胎和原始 ESCs(nESCs)中，PRC1.6 DNA 结合亚基 MGA/MAX/E2F6 结合的生殖系基因的低甲基化启动子富含 RING1B 依赖性 H2AK119ub1 和 H3K9me3。因此，nESCs 中这些基因的抑制对 PRC1.6 的依赖性大于 DNAme。相比之下，GGD 基因在类上胚层细胞 (EpiLCs) 中高度甲基化，其沉默依赖于 SETDB1、PRC1.6/RING1B 和 DNAme，H3K9me3 和 DNAme 的建立依赖于 MGA 结合。因此，GGD 基因最初被 PRC1.6 抑制，随后在植入后的胚胎中进行 DNAme 结合。
