Repression of germline genes by PRC1.6 and SETDB1 in the early embryo precedes DNA methylation-mediated silencing

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Abstract
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.
Funding Information
  • Uehara Memorial Foundation (Postdoctoral fellowship)
  • Nakatani Foundation for Advancement of Measuring Technologies in Biomedical Engineering (Technology exchange grant)
  • MEXT | Japan Society for the Promotion of Science (17KK0185, JP40225446)
  • Mother and Child Health Foundation (R01-1)
  • Sumitomo Foundation (200304)
  • Gouvernement du Canada | Instituts de Recherche en Santé du Canada | CIHR Skin Research Training Centre (PJT-153049)
  • Gouvernement du Canada | Canadian Institutes of Health Research (PJT-166170)
  • Gouvernement du Canada | Natural Sciences and Engineering Research Council of Canada (RGPIN-2021-02808)

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