Wei Xie’s group and joint team published research in Nature Genetics on SETD2 regulating establishment of maternal epigenome, genomic imprinting and embryonic development
A joint team led by Prof. Wei Xie from Tsinghua University, Prof. Li Li from Ren Ji Hospital at Shanghai Jiao Tong University, and Prof. Wei Li from Institute of Zoology at Chinese Academy of Sciences, has revealed how the mammalian oocyte epigenome is established through extensive cross-talk among epigenetic modifications, and how a functional maternal epigenome in turn has a profound impact on embryonic development. Their findings, published in Nature Genetics on April 29, 2019, not only demonstrated dynamic interactions between epigenetic marks during oogenesis, but also revealed SETD2 as a crucial player in establishing the maternal epigenome that in turn controls embryonic development.
The mammalian oocyte epigenome plays critical roles in gametogenesis and embryogenesis. Yet, how it is established remains elusive. By depleting Setd2, a histone methyltransferase for H3K36me3, during mouse oogenesis, the researchers discovered that the deficiency of SETD2 leads to a compromised oogenesis and to infertility. Further investigation revealed extensive alterations of the oocyte epigenome, including the loss of H3K36me3, failure in establishment of correct DNA methylome, invasion of H3K4me3 and H3K27me3 into former H3K36me3 territories, and aberrant acquisition of H3K4me3 instead of DNA methylation at imprinting control regions. More importantly, maternal depletion of SETD2 results in oocyte maturation defects and subsequent 1-cell arrest after fertilization. Carefully-designed chromatin-cytosol swapping experiments revealed that the preimplantation arrest is mainly due to maternal cytosolic defect, as it can be largely rescued by wild-type 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.
Prof. Wei Xie from School of Life Science at Tsinghua University, Prof. Li Li from Ren Ji Hospital at Shanghai Jiao Tong University, and Prof Wei Li from Institute of Zoology at Chinese Academy of Sciences are the co-corresponding authors of this work. Postdoc fellow Qianhua Xu from CLS program at Tsinghua university, Ph.D student Yunlong Xiang from CLS program, Ph.D student Qiujun Wang from School of Life Sciences at Tsinghua University, and Postdoc fellow Leyun Wang from Institute of Zoology at Chinese Academy of Sciences are the co-first authors of this work. Prof. Matthew C. Lorincz and Prof. Louis Lefebvre from University of British Columbia, Prof. Min Wu from Wuhan University, Prof. Cheryl Lyn Walker from Baylor College of Medicine, and Prof. Eric Jonasch from University of Texas MD Anderson Cancer Center also made important contributions to this study. This work was supported by the National Natural Science Foundation of China, the National Key R&D Program of China, the National Basic Research Program of China, Beijing Municipal Science & Technology Commission, Science and Technology Commission of Shanghai Municipality, the THU-PKU Center for Life Sciences, the Canadian Institutes of Health Research, National Cancer Institute, and National Institutes of Health, the Innovation Research Plan from the Shanghai Municipal Education Commission and the State Key Laboratory of Oncogenes and Related Genes. Prof. Wei Xie is also a HHMI International Research Scholar.
SETD2 regulates oocyte epigenome, genomic imprinting, and embryonic development
(From School of Life Sciences)