TY - JOUR
T1 - SETD2 regulates the maternal epigenome, genomic imprinting and embryonic development
AU - Xu, Qianhua
AU - Xiang, Yunlong
AU - Wang, Qiujun
AU - Wang, Leyun
AU - Brind’Amour, Julie
AU - Bogutz, Aaron Blair
AU - Zhang, Yu
AU - Zhang, Bingjie
AU - Yu, Guang
AU - Xia, Weikun
AU - Du, Zhenhai
AU - Huang, Chunyi
AU - Ma, Jing
AU - Zheng, Hui
AU - Li, Yuanyuan
AU - Liu, Chao
AU - Walker, Cheryl Lyn
AU - Jonasch, Eric
AU - Lefebvre, Louis
AU - Wu, Min
AU - Lorincz, Matthew C.
AU - Li, Wei
AU - Li, Li
AU - Xie, Wei
N1 - Funding Information:
We thank members of the Xie laboratory for their comments during the preparation of the manuscript. We thank F. Gao for providing the Gdf9-Cre mice. We are thankful for the support provided by the animal core, sequencing core and biocomputing facilities at Tsinghua University. This work was funded by the National Natural Science Foundation of China (grant nos. 31422031 and 31725018 to W.Xie; grant no. 81772938 to L.Li), National Key R&D Program of China (grant no. 2016YFC0900300 to W.Xie), the National Basic Research Program of China (grant no. 2015CB856201 to W.Xie), Beijing Municipal Science & Technology Commission (grant no. Z181100001318006 to W.Xie), Science and Technology Commission of Shanghai Municipality (grant nos. 16140902100 and 18140902700 to L.Li), the THU-PKU Center for Life Sciences (W.Xie), by the Canadian Institutes of Health Research (grant no. MOP-133417 to M.C.L. and grant no. MOP-119357 to L.Lefebvre) and by National Cancer Institute, National Institutes of Health (grant no. CA231993 and CA203012 to C.L.W.). Q.X. is supported by postdoctoral fellowships from the Tsinghua-Peking Joint Center for Life Sciences. L.Li is supported by an Innovation Research Plan from the Shanghai Municipal Education Commission (grant no. ZXGF082101) and funds from State Key Laboratory of Oncogenes and Related Genes (grant no. KF01801). W.Xie is a recipient of an HHMI International Research Scholar award.
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2019/5/1
Y1 - 2019/5/1
N2 - The oocyte epigenome plays critical roles in mammalian gametogenesis and embryogenesis. Yet, how it is established remains elusive. Here, we report that histone-lysine N-methyltransferase SETD2, an H3K36me3 methyltransferase, is a crucial regulator of the mouse oocyte epigenome. Deficiency in Setd2 leads to extensive alterations of the oocyte epigenome, including the loss of H3K36me3, failure in establishing the correct DNA methylome, invasion of H3K4me3 and H3K27me3 into former H3K36me3 territories and aberrant acquisition of H3K4me3 at imprinting control regions instead of DNA methylation. Importantly, maternal depletion of SETD2 results in oocyte maturation defects and subsequent one-cell arrest after fertilization. The preimplantation arrest is mainly due to a maternal cytosolic defect, since it can be largely rescued by normal oocyte cytosol. However, chromatin defects, including aberrant imprinting, persist in these embryos, leading to embryonic lethality after implantation. Thus, these data identify SETD2 as a crucial player in establishing the maternal epigenome that in turn controls embryonic development.
AB - The oocyte epigenome plays critical roles in mammalian gametogenesis and embryogenesis. Yet, how it is established remains elusive. Here, we report that histone-lysine N-methyltransferase SETD2, an H3K36me3 methyltransferase, is a crucial regulator of the mouse oocyte epigenome. Deficiency in Setd2 leads to extensive alterations of the oocyte epigenome, including the loss of H3K36me3, failure in establishing the correct DNA methylome, invasion of H3K4me3 and H3K27me3 into former H3K36me3 territories and aberrant acquisition of H3K4me3 at imprinting control regions instead of DNA methylation. Importantly, maternal depletion of SETD2 results in oocyte maturation defects and subsequent one-cell arrest after fertilization. The preimplantation arrest is mainly due to a maternal cytosolic defect, since it can be largely rescued by normal oocyte cytosol. However, chromatin defects, including aberrant imprinting, persist in these embryos, leading to embryonic lethality after implantation. Thus, these data identify SETD2 as a crucial player in establishing the maternal epigenome that in turn controls embryonic development.
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U2 - 10.1038/s41588-019-0398-7
DO - 10.1038/s41588-019-0398-7
M3 - Article
C2 - 31040401
AN - SCOPUS:85065186828
SN - 1061-4036
VL - 51
SP - 844
EP - 856
JO - Nature Genetics
JF - Nature Genetics
IS - 5
ER -