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

Kentaro Mochizuki, Jafar Sharif, Kenjiro Shirane, Kousuke Uranishi, Aaron B. Bogutz, Sanne M. Janssen, Ayumu Suzuki, Akihiko Okuda, Haruhiko Koseki and Matthew C. Lorincz ()
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Kentaro Mochizuki: University of British Columbia
Jafar Sharif: RIKEN Center for Integrative Medical Sciences (IMS)
Kenjiro Shirane: University of British Columbia
Kousuke Uranishi: Saitama Medical University
Aaron B. Bogutz: University of British Columbia
Sanne M. Janssen: University of British Columbia
Ayumu Suzuki: Saitama Medical University
Akihiko Okuda: Saitama Medical University
Haruhiko Koseki: RIKEN Center for Integrative Medical Sciences (IMS)
Matthew C. Lorincz: University of British Columbia

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-27345-x

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