Global rewiring of cis-regulatory units upon lineage commitment of human embryonic stem cells. Homo sapiens

Lineage commitment is characterised by orchestrated changes in gene expression and chromatin state. Long-range elements such as enhancers coordinate lineage-specific transcriptional programmes by engaging in DNA looping interactions with target promoters. However, the target genes of most long-range elements remain unknown, hindering an integrated understanding of cis-regulatory gene control. Here, we generate a high-resolution atlas of chromosomal interactions involving ~22,000 gene promoters in human pluripotent and lineage-committed cells, identifying putative target genes for known and predicted enhancer elements. We jointly consider promoters and their associated interacting regions as “cis-regulatory units” that potentially integrate and stabilise regulatory inputs from individual elements. We reveal extensive dynamics of cis-regulatory units upon lineage commitment, including the acquisition and loss of promoter interactions, as well as chromatin state changes at preformed interactions. Finally, we show that reconfiguration of cis-regulatory units associates with changes in target gene expression. Our results therefore provide a high-resolution view of promoter interactome dynamics during lineage commitment and provide insights into the mechanisms of developmental transcriptional regulation. Overall design: Two human ESC CHi-C biological replicates were generated (comprising 1 and 2 technical replicates) and a human ESC Hi-C dataset. Two human NEC CHi-C biological replicates were generated and a human NEC Hi-C dataset. Two RNA-Seq biological replicates for both human ESC and NEC were generated.