TY - JOUR
T1 - Repression of germline genes by PRC1.6 and SETDB1 in the early embryo precedes DNA methylation-mediated silencing
AU - Mochizuki, Kentaro
AU - Sharif, Jafar
AU - Shirane, Kenjiro
AU - Uranishi, Kousuke
AU - Bogutz, Aaron B.
AU - Janssen, Sanne M.
AU - Suzuki, Ayumu
AU - Okuda, Akihiko
AU - Koseki, Haruhiko
AU - Lorincz, Matthew C.
N1 - Funding Information:
We thank J. Brind’Amour, J. Richard Albert, and K. Jensen for helpful discussions and technical assistance; L. Lefebvre (UBC) for critical reading of the manuscript; and T. Stach, R. Vander Werff, Y. Chung, and Y. Zhao (BRC-seq, UBC) for deep sequencing and J. Wong and A. Johnson (ubcFLOW, UBC) for cell sorting. M.C.L. was supported by CIHR grants PJT-153049 and PJT-166170, and NSERC Discovery Grants RGPIN-2021-02808. K.M. was a recipient of a Uehara Memorial Foundation postdoctoral fellowship, a Nakatani Foundation technology exchange grant, a MEXT Fund for the Promotion of Joint International Research 17KK0185, a Mother & Child Health Foundation grant R01-1, and a Sumitomo Foundation grant 200304. This work was also supported by MEXT KAKENHI JP40225446 to J.S. and H.K.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-021-27345-x
DO - 10.1038/s41467-021-27345-x
M3 - Article
C2 - 34857746
AN - SCOPUS:85120891434
VL - 12
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 7020
ER -