Comprehensive identification of fetal cis-regulatory elements in the human genome by single-cell multi-omics analysis

The regulatory programs driving early organogenesis in human is complex and still poorly understood. We performed parallel profiling of gene expression and chromatin accessibility to 28 human fetal tissue samples representing 14 organs in the first trimester. Collectively, we have generated 415,793 single-cell profiles. By integration analysis of transcriptome and chromatin accessibility, we detected 225 distinct cell types and 848,475 candidate accessible cis-regulatory elements (aCREs). By linking regulatory elements to their putative target genes, we identified not only 108,699 enhancers, but also 23,392 silencers elements. We uncovered thousands of genes regulated by both enhancers and silencers in an organ or cell-type-specific manner. Furthermore, our unique approach revealed a substantial proportion of distal DNA elements are transcribed CREs (tCREs), which show both open chromatin signal and transcription initiation activity of non-coding transcript. The landscape of fetal cis-regulatory elements facilitates the interpretation of the genetic variant of complex disease and infer the cell type of origin for cancer. Overall, our data provide a comprehensive map of the fetal cis-regulatory elements at single-cell resolution and a valuable resource for future study of human development and disease.