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.
Highlights
While the life’s evolution from simplicity to complexity can benefit living beings on survival and reproduction, this transition put them under tremendous pressures and stresses, such as demanded requirements of nutrient redistribution between cells and sexual propagation[1,2]
The results showed that, while the efficiency of Setd[2] knockdown was verified by the significant inhibition of the enhanced green fluorescent protein (EGFP) reporter and the dramatic decrease of H3K36me[3] (Supplementary Fig. S2a–c), the morphant embryos developed and grew normally (Supplementary Fig. S2b, d)
The loss of H3K36me[3] provides another line of evidence to exclude the genetic compensation effect and, in combination with previous studies, these results demonstrate that, while the specific role of Setd[2] as the major enzyme for H3K36me[3] is evolutionarily conserved, the functions of Setd[2] and H3K36me[3] are differentially required for the viability of different vertebrate animals
Summary
While the life’s evolution from simplicity to complexity can benefit living beings on survival and reproduction, this transition put them under tremendous pressures and stresses, such as demanded requirements of nutrient redistribution between cells and sexual propagation[1,2]. Other tissue-specific studies in mice indicate that Setd[2] regulates hematopoietic stem cell[40,41] and bone marrow mesenchymal stem cell functions[42], V(D)J recombination in lymphocytes[43,44], as well as endodermal differentiation of embryonic stem cells[45], though these functions may not necessarily be related to viability of the mice These observations raise a question of how the functional requirements of H3K36me[3] and Set2/SETD2 in the specific developmental stages have emerged through the evolution of life from simplicity to complexity. A close comparison between these model organisms suggests that the apparently differential requirements of H3K36me[3] and Set2/SETD2 in different organisms are well paralleled and likely associated with intrinsic and/or extrinsic stresses experienced by the organisms through development
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