Highly interconnected enhancer communities control lineage-determining genes in human mesenchymal stem cells

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Adipocyte differentiation is driven by waves of transcriptional regulators that reprogram the enhancer landscape and change the wiring of the promoter interactome. Here, we use high-throughput chromosome conformation enhancer capture to interrogate the role of enhancer-to-enhancer interactions during differentiation of human mesenchymal stem cells. We find that enhancers form an elaborate network that is dynamic during differentiation and coupled with changes in enhancer activity. Transcription factors (TFs) at baited enhancers amplify TF binding at target enhancers, a phenomenon we term cross-interaction stabilization of TFs. Moreover, highly interconnected enhancers (HICE) act as integration hubs orchestrating differentiation by the formation of three-dimensional enhancer communities, inside which, HICE, and other enhancers, converge on phenotypically important gene promoters. Collectively, these results indicate that enhancer interactions play a key role in the regulation of enhancer function, and that HICE are important for both signal integration and compartmentalization of the genome.

Original languageEnglish
JournalNature Genetics
Volume52
Issue number11
Pages (from-to)1227-1238
ISSN1061-4036
DOIs
Publication statusPublished - 1. Nov 2020

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