Journal
NATURE COMMUNICATIONS
Volume 11, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-020-19877-5
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Funding
- Spanish Ministry of Economy and Competitiveness [BFU2014-53543-P, BFU2017-85420-R]
- Junta de Andalucia [BIO-321]
- Fundacion Vencer El Cancer (VEC)
- European Union (FEDER)
- Junta de Andalucia
- FERO Foundation
- La Caixa Foundation [LCF/PR/PR12/51070001]
- Cellex Foundation
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The Transforming Growth Factor-beta (TGF beta) signaling pathway controls transcription by regulating enhancer activity. How TGF beta-regulated enhancers are selected and what chromatin changes are associated with TGF beta-dependent enhancers regulation are still unclear. Here we report that TGF beta 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 TGF beta. This enhancer opening depends on both the canonical and non-canonical TGF beta pathways. Most TGF beta-regulated genes are located around enhancers regulated in the same way, often creating domains of several co-regulated genes that we term TGF beta regulatory domains (TRD). CRISPR-mediated inactivation of enhancers within TRDs impairs TGF beta-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.
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