1. Academic Validation
  2. setd2 knockout zebrafish is viable and fertile: differential and developmental stress-related requirements for Setd2 and histone H3K36 trimethylation in different vertebrate animals

setd2 knockout zebrafish is viable and fertile: differential and developmental stress-related requirements for Setd2 and histone H3K36 trimethylation in different vertebrate animals

  • Cell Discov. 2020 Oct 20;6:72. doi: 10.1038/s41421-020-00203-8.
Dian-Jia Liu  # 1 Fan Zhang  # 1 Yi Chen  # 1 Yi Jin 1 Yuan-Liang Zhang 1 Shu-Bei Chen 1 2 3 Yin-Yin Xie 1 Qiu-Hua Huang 1 Wei-Li Zhao 1 Lan Wang 2 Peng-Fei Xu 4 Zhu Chen 1 Sai-Juan Chen 1 Bing Li 5 Aijun Zhang 6 Xiao-Jian Sun 1
Affiliations

Affiliations

  • 1 Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 2 CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
  • 3 School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.
  • 4 Division of Human Reproduction and Developmental Genetics, Women's Hospital, and Institute of Genetics and Department of Genetics, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058 China.
  • 5 Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 6 Reproductive Medical Center, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • # Contributed equally.
Abstract

Setd2 is the only Enzyme that catalyzes histone H3 lysine 36 trimethylation (H3K36me3) on virtually all actively transcribed protein-coding genes, and this mechanism is evolutionarily conserved from yeast to human. Despite this widespread and conserved activity, Setd2 and H3K36me3 are dispensable for normal growth of yeast but are absolutely required for mammalian embryogenesis, such as oocyte maturation and embryonic vasculogenesis in mice, raising a question of how the functional requirements of Setd2 in specific developmental stages have emerged through evolution. Here, we explored this issue by studying the essentiality and function of Setd2 in zebrafish. Surprisingly, the setd2-null zebrafish are viable and fertile. They show Mendelian birth ratio and normal embryogenesis without vascular defect as seen in mice; however, they have a small body size phenotype attributed to insufficient energy metabolism and protein synthesis, which is reversable in a nutrition-dependent manner. Unlike the sterile Setd2-null mice, the setd2-null zebrafish can produce functional sperms and oocytes. Nonetheless, related to the requirement of maternal Setd2 for oocyte maturation in mice, the second generation of setd2-null zebrafish that carry no maternal setd2 show decreased survival rate and a developmental delay at maternal-to-zygotic transition. Taken together, these results indicate that, while the phenotypes of the setd2-null zebrafish and mice are apparently different, they are matched in parallel as the underlying mechanisms are evolutionarily conserved. Thus, the differential requirements of Setd2 may reflect distinct viability thresholds that associate with intrinsic and/or extrinsic stresses experienced by the organism through development, and these epigenetic regulatory mechanisms may serve as a reserved source supporting the evolution of life from simplicity to complexity.

Keywords

Developmental biology; Epigenetics.

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