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Wei Xie’s group, Yong Guo’s group, and Wei Li’s group published research in Science Advances on evolutionary analyses in epigenetic reprogramming in early mammalian development
  A joint team led by Prof. Wei Xie from Tsinghua University, Prof. Yong Guo from Beijing University of Agriculture, and Prof. Wei Li from Institute of Zoology at Chinese Academy of Sciences, has systematically studied the evolutionary conservation of epigenetic transmission and reprogramming among five species during mammalian early development. Their findings, published in Science Advances on November 24, 2021, not only greatly deepen our fundamental understanding on how the life clock is reset through fertilization, but also shed light on to what extent knowledge learned from model organisms, such as mouse, can be directly translated to human.

  Epigenetic reprogramming in early mammalian development is the key to convert two highly specialized gametes to a totipotent embryo. Most of our knowledge is derived from animal models such as mouse, due to the scarcity of research samples from early embryos and the ethical limit of human embryos. However, the conservation of epigenetic inheritance and reprogramming during early development remains poorly defined. Using a series of highly sensitive chromatin analysis technologies, the researchers systematically investigated the DNA methylomes and several key histone marks (H3K4me3, H3K27me3, H3K36me2 and H3K36me3) in the gametes and preimplantation embryos among five mammalian species, including human, bovine, porcine, rat, and mouse. Through integrative analyses of these and previously published datasets, the researchers revealed several exciting findings. First of all, no single animal model can fully recapitulate epigenetic reprogramming in human oocytes and early embryos, cautioning direct data extrapolation across species. In rodent oocytes, DNA methylation, including that in imprinting control regions, is established in a transcription-dependent manner. Unexpectedly, widespread hypermethylation occurs in both transcribed and non-transcribed regions in the oocytes of porcine and bovine. Such widespread DNA hypermethylation parallels H3K36me2 and H3K36me3, which are known to be essential in establishing DNA methylation in mouse gametes. Notably, H3K36me2 and H3K36me3 mark similar regions in the oocytes of porcine and bovine, but not in rodents, indicating both conservation and divergence in mechanisms instructing de novo DNA methylation. However, hypomethylated domains do exist in regions in porcine and bovine oocytes, featured by unusually high CG density over stretches of megabases and are thus designated CpG continents (CGCs). CGCs are prevalent in porcine, bovine and human, but are rare in rodents. CGCs preferentially harbor developmental genes and imprinting control regions in porcine and bovine, raising a possibility that they might serve as “safe harbors” to ensure the unmethylated states of key regulatory elements.

  For histone modifications, the researchers found that non-canonical, broad distal domains of H3K4me3 and H3K27me3 are present in all oocytes except those from human. While such broad H3K4me3 is reset to a canonical pattern after ZGA, oocyte H3K27me3 in rodents, but not other species, survives beyond ZGA, leading to presumably rodent-specific H3K27me3-mediated imprinting. Possibly as a result, regulatory elements are preferentially excluded from H3K27me3 in oocytes in mouse. Failure to do so leads to aberrant repression of embryonic genes. Despite diverse mammalian innovations, a conserved theme of epigenetic inheritance and reprogramming may center on a delicate “to-methylate-or-not” balance in establishing imprints while protecting other key regulatory regions. 

  Prof. Wei Xie from School of Life Science at Tsinghua University, Prof. Yong Guo from Beijing University of Agriculture, and Prof. Wei Li from Institute of Zoology at Chinese Academy of Sciences are the co-corresponding authors of this work. Postdoc fellows Xukun Lu, Yu Zhang from the THU-PKU Center for Life Sciences program, research associate Lijuan Wang 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. Dr. Huili Wang from Institute of Animal Science at Jiangsu Academy of Agricultural Sciences, Dr. Xiangguo Wang and Prof. Hemin Ni from Beijing University of Agriculture also made important contributions to this study. This work was supported by the National Natural Science Foundation of China, the National Key Research and Development Program of China, the THU-PKU Center for Life Sciences, Beijing Municipal Science & Technology Commission, and the Strategic Priority Research Program of the Chinese Academy of Sciences. Prof. Wei Xie is also an HHMI International Research Scholar.

  Conservation and divergence of epigenetic reprogramming and genomic imprinting in mammalian early development. a, Oocyte DNA methylation (relatively high in human, bovine and porcine and low in rodents) is decreased during early development in all species, except that in imprinted regions. Non-canonical H3K4me3 and H3K27me3 are present in non-human species, but only H3K27me3 in rodents can survive beyond ZGA. b, DNA methylation in oocytes (correlates with H3K36me3 and H3K36me2 in bovine and porcine) at maternal imprints. Paternal imprints are hypomethylated residing in non-transcribed intergenic regions (in CGCs in bovine and porcine). H3K27me3 likely mediates non-canonical imprinting only in rodents. H3K4me3 and H3K27me3 colocalize in bovine and porcine, but are largely separated in rodent oocytes. A balance of the establishment of imprints and protection of non-imprints in oocytes is proposed to exist across mammalian species.


Link: https://www.science.org/doi/10.1126/sciadv.abi6178




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