Single-nucleus chromatin accessibility landscape in mouse preimplantation embryos

The initiation of mammalian life begins with fertilization, when terminally committed gametes are reprogrammed into a totipotent state. However, the mechanisms of chromatin reorganization within a single-nucleus during this reprogramming remain shrouded in mystery. Here we developed a single-nucleus assay for transposase-accessible chromatin with high throughput sequencing (snATAC-seq) for preimplantation embryos, and profiling over 3,000 blastomeres from oocyte to blastocyst. We observed dramatic dynamics in chromatin accessibility from the zygote to the 2-cell stage, corresponding to a crucial event in preimplantation development: zygotic genome activation (ZGA). To date, only a handful of transcription factors (TFs) involved in ZGA regulation have been identified. Surprisingly, we discovered 148 significantly enriched ZGA-specific TFs, with nearly all well-studied ZGA regulators including Obox, Nr5a2, Zscan4, and Dux. Notably, accessible chromatin extensively overlaps with transposable elements, particularly B1, which contains numerous binding motifs for TFs associated with ZGA regulation. And a de novo TF family, "AT-rich interactive domain" (ARID), were significantly enriched in both accessible chromatin and B1 in ZGA stages. Taken together, our study offered the first highly sensitive single-nuclear chromatin accessibility maps of mouse preimplantation embryos and provided new insights into the programmatic regulation between cis-elements and trans-regulators in this process.