Single-cell multi-omics delineates the dynamics of distinct epigenetic codes coordinating mouse gastrulation.

Gastrulation represents a crucial stage in embryonic development and is tightly controlled by a complex network involving epigenetic reprogramming. However, the molecular coordination among distinct epigenetic layers entailing the progressive restriction of lineage potency remains unclear. Here, we present a multi-omics map of H3K27ac and H3K4me1 single-cell ChIP-seq profiles of mouse embryos collected at six sequential time points. Significant epigenetic priming, as reflected by H3K27ac signals, is evident, yet asynchronous cell fate commitment of each germ layer at distinct histone modification levels are observed. Integrated scRNA-seq and single-cell ChIP-seq analysis unveil a "time lag" transition pattern between enhancer activation and gene expression during germ-layer specification. Notably, by utilizing the H3K27ac and H3K4me1 co-marked active enhancers, we construct a gene regulatory network centered on pivotal transcription factors, highlighting the potential critical role of Cdkn1c in mesoderm lineage specification. Together, our study broadens the current understanding of intricate epigenetic regulatory networks governing mouse gastrulation and sheds light on their relevance to congenital diseases.