Dynamic pattern of histone H3 core acetylation in human early embryos

After fertilization, highly differentiated sperm and oocyte are reprogrammed to totipotent embryo, which subsequently cleavages and develops into an individual through spatial-temporal differentiation. Histone modifications play critical roles to coordinate with other reprogramming events in early stages of embryogenesis. However, most of studies focus on modifications at N-terminus of histones, those at nucleosome core were not well understood. Here, we characterize the three key acetylation events in the histone H3 core, H3K56/K64/K122ac, in early human embryos. The three residues localize at DNA entry-exit position of the nucleosome. Globally, H3K56ac, H3K64ac and H3K122ac were detectable throughout preimplantation stages, with H3K64ac levels being relatively stronger and H3K122ac levels being much weaker. Besides, H3K56ac level had a peak at two-cell stage. Moreover, we found that LINEs also peak at two-cell stage, and H3K56ac was enriched at young LINE-1 in human ESCs, supporting that H3K56ac is an important driving force for young LINE-1 activation in human preimplantation embryos. Our results suggest that acetylation in the nucleosome core of histone H3 is dynamic and various during preimplantation development, and may drive diverse chromatin remodeling events in this developmental window.

受精后，高度分化的精子与卵母细胞经重编程转变为全能性胚胎，随后通过卵裂与时空特异性分化发育为完整个体。组蛋白修饰（histone modifications）在胚胎发生早期可协同其他重编程事件发挥关键调控作用。然而，绝大多数现有研究多聚焦于组蛋白N端的修饰，而针对核小体核心区域的修饰机制仍有待深入解析。本研究针对人类早期胚胎中组蛋白H3核心区域的三处关键乙酰化修饰位点——H3K56ac、H3K64ac及H3K122ac——开展了系统表征。这三个残基均定位于核小体的DNA进出位点。全局水平检测结果显示，H3K56ac、H3K64ac与H3K122ac在整个植入前发育阶段均可被检测到，其中H3K64ac的信号强度相对更高，而H3K122ac的信号则显著较弱。此外，H3K56ac的修饰水平在二细胞期达到峰值。进一步研究发现，长散在核元件（LINEs）的表达同样在二细胞期达到峰值；且H3K56ac在人类胚胎干细胞的年轻LINE-1元件上富集，这表明H3K56ac是人类植入前胚胎中年轻LINE-1激活的重要驱动因素。本研究结果表明，组蛋白H3核小体核心区域的乙酰化修饰在植入前发育过程中呈现动态多样的变化模式，可能在该发育窗口内介导多种染色质重塑事件。