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

Author

Listed:
  • Kentaro Mochizuki

    (University of British Columbia)

  • Jafar Sharif

    (RIKEN Center for Integrative Medical Sciences (IMS))

  • Kenjiro Shirane

    (University of British Columbia
    Kyushu University)

  • 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)
    Chiba University)

  • Matthew C. Lorincz

    (University of British Columbia)

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.

Suggested Citation

  • Kentaro Mochizuki & Jafar Sharif & Kenjiro Shirane & Kousuke Uranishi & Aaron B. Bogutz & Sanne M. Janssen & Ayumu Suzuki & Akihiko Okuda & Haruhiko Koseki & Matthew C. Lorincz, 2021. "Repression of germline genes by PRC1.6 and SETDB1 in the early embryo precedes DNA methylation-mediated silencing," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27345-x
    DOI: 10.1038/s41467-021-27345-x
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