Single-cell multi-omics sequencing of human early embryos

DNA methylation, chromatin states, and their interrelationships represent critical epigenetic information, but those are largely unknown in human early embryos. Here, we apply scCOOL-seq (Chromatin Overall Omic-scale Landscape Sequencing) to generate a genome-wide map of DNA methylation and chromatin accessibility at single-cell resolution during human preimplantation development. Unlike in mice, the chromatin of paternal genome is already more open than that of maternal genome at the mid-zygote stage in humans, and this state is maintained until the 4-cell stage. After fertilization, genes with high variations in DNA methylation and those with high variations in chromatin accessibility tend to be two different sets. Furthermore, 1,797 (35%) out of 5,155 widely open chromatin regions in promoters closed when transcription activity was inhibited, indicating a feedback mechanism between transcription and open chromatin maintenance. Our work paves the way for dissecting the complex, yet highly coordinated, epigenetic reprogramming during human preimplantation development.

DNA甲基化、染色质状态及其相互关联是关键的表观遗传信息，但此类信息在人类早期胚胎中大多仍未被阐明。本研究采用单细胞染色质整体多组学全景测序（scCOOL-seq）技术，构建了人类植入前发育过程中全基因组范围、单细胞分辨率的DNA甲基化与染色质可及性图谱。与小鼠模型不同，人类受精卵中期的父本基因组染色质可及性已高于母本基因组，且这一状态可维持至4细胞期。受精后，DNA甲基化变异显著的基因与染色质可及性变异显著的基因往往分属不同的基因集。进一步研究显示，在5155个启动子区域的广泛开放染色质位点中，有1797个（占比35%）在转录活性被抑制时发生闭合，这表明转录与开放染色质维持之间存在反馈调控机制。本研究为解析人类植入前发育过程中复杂且高度协同的表观遗传重编程进程铺平了道路。