TGFβ promotes widespread enhancer chromatin opening and operates on genomic regulatory domains

Abstract

Cromatina; Informàtica del genoma; Transcripció

Cromatina; Informática del genoma; Transcripción

Chromatin; Genome informatics; Transcription

The Transforming Growth Factor-β (TGFβ) signaling pathway controls transcription by regulating enhancer activity. How TGFβ-regulated enhancers are selected and what chromatin changes are associated with TGFβ-dependent enhancers regulation are still unclear. Here we report that TGFβ treatment triggers fast and widespread increase in chromatin accessibility in about 80% of the enhancers of normal mouse mammary epithelial-gland cells, irrespective of whether they are activated, repressed or not regulated by TGFβ. This enhancer opening depends on both the canonical and non-canonical TGFβ pathways. Most TGFβ-regulated genes are located around enhancers regulated in the same way, often creating domains of several co-regulated genes that we term TGFβ regulatory domains (TRD). CRISPR-mediated inactivation of enhancers within TRDs impairs TGFβ-dependent regulation of all co-regulated genes, demonstrating that enhancer targeting is more promiscuous than previously anticipated. The area of TRD influence is restricted by topologically associating domains (TADs) borders, causing a bias towards co-regulation within TADs.

This work was funded by the Spanish Ministry of Economy and Competitiveness (BFU2014-53543-P and BFU2017-85420-R to J.C. Reyes), the Junta de Andalucía (BIO-321), “Fundación Vencer El Cancer” (VEC) and the European Union (FEDER). CABIMER is a Center partially funded by the Junta de Andalucía. S.P was supported by the FERO Foundation, La Caixa Foundation (LCF/PR/PR12/51070001) and Cellex Foundation.