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Nat Genet. 2019 May;51(5):844-856. doi: 10.1038/s41588-019-0398-7. Epub 2019 Apr 29.

SETD2 regulates the maternal epigenome, genomic imprinting and embryonic development.

Author information

1
Center for Stem Cell Biology and Regenerative Medicine, MOE Key Laboratory of Bioinformatics, THU-PKU Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China.
2
State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
3
Department of Medical Genetics, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada.
4
Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX, USA.
5
Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
6
Hubei Key Laboratory of Cell Homeostasis, Hubei Key Laboratory of Enteropathy, College of Life Sciences, Wuhan University, Wuhan, China.
7
State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China. liwei@ioz.ac.cn.
8
State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China. lil@sjtu.edu.cn.
9
Center for Stem Cell Biology and Regenerative Medicine, MOE Key Laboratory of Bioinformatics, THU-PKU Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China. xiewei121@tsinghua.edu.cn.

Abstract

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.

PMID:
31040401
DOI:
10.1038/s41588-019-0398-7
[Indexed for MEDLINE]

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