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.

Setd2是唯一一种催化几乎所有活跃转录的蛋白编码基因上的组蛋白H3赖氨酸36三甲基化（H3K36me3）的酶，从酵母到人在进化上都是保守的。尽管具有这种广泛且保守的活性，Setd2和H3K36me3对于酵母的正常生长是必不可少的，但对于哺乳动物胚胎发生（例如小鼠的卵母细胞成熟和胚胎血管生成）绝对是必需的，这引发了一个问题，即Setd2在特定发育阶段的功能需求通过进化而出现。在这里，我们通过研究Setd2在斑马鱼中的必要性和功能来探讨这个问题。令人惊讶的是，setd2-零斑马鱼是可行的和肥沃的。它们显示了孟德尔出生率和正常的胚胎发生，而小鼠没有血管缺陷。然而，由于能量代谢和蛋白质合成不足，它们具有较小的表型，可以通过营养依赖的方式逆转。与无菌的Setd2- null小鼠不同，setd2- null斑马鱼可以产生功能性精子和卵母细胞。但是，与母本Setd2对小鼠卵母细胞成熟的需求有关，第二代不携带母本setd2的setd2-空斑马鱼表现出降低的存活率和母体向合子过渡的发育延迟。两者合计，这些结果表明，虽然setd2- null斑马鱼和小鼠的表型明显不同，但由于潜在的机制在进化上是保守的，它们平行匹配。因此，Setd2的差异需求可能反映了不同的生存能力阈值，这些阈值与生物体通过发育经历的内在和/或外在压力相关，并且这些表观遗传调控机制可以作为支持生命从简单到复杂的进化的保留来源。