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

Jose A. Guerrero-Martínez, María Ceballos-Chávez, Florian Koehler, Sandra Peiró and Jose C. Reyes ()
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Jose A. Guerrero-Martínez: Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, Consejo Superior de Investigaciones Científicas-Universidad de Sevilla-Universidad Pablo de Olavide (CSIC-USE-UPO), Avenida Americo Vespucio 24
María Ceballos-Chávez: Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, Consejo Superior de Investigaciones Científicas-Universidad de Sevilla-Universidad Pablo de Olavide (CSIC-USE-UPO), Avenida Americo Vespucio 24
Florian Koehler: German Cancer Research Center
Sandra Peiró: Vall d’Hebron Institute of Oncology (VHIO)
Jose C. Reyes: Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, Consejo Superior de Investigaciones Científicas-Universidad de Sevilla-Universidad Pablo de Olavide (CSIC-USE-UPO), Avenida Americo Vespucio 24

Nature Communications, 2020, vol. 11, issue 1, 1-20

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-19877-5

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