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. In total, we analyzed 265 single cells (13 sperm, 9 oocytes, 10 zygotes, 14 2-cell blastomeres, 26 4-cell blastomeres, 48 8-cell blastomeres, 25 morulae blastomeres, 50 ICM, 48 TE and 22 hESCs) as well as 23 alpha-Amanitin treated 8-cell blastomeres.