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

• Published in: Nature communications 2020-12, Vol.11 (1), p.6196-6196, Article 6196
• Main Authors: Guerrero-Martínez, Jose A., Ceballos-Chávez, María, Koehler, Florian, Peiró, Sandra, Reyes, Jose C.
• Format: Article
• Language: English
• Subjects: 14/19; 38/39; 45; 45/15; 45/41; 45/77; 45/91; 631/114/2785; 631/337/100; 631/337/572; 631/337/572/2102; 96/21; 96/95; Animals; Chromatin; Chromatin - metabolism; CRISPR; Domains; Enhancer Elements, Genetic; Enhancers; Gene Expression Regulation; Gene regulation; Genes; Genome; Growth factors; HEK293 Cells; Humanities and Social Sciences; Humans; Inactivation; MCF-7 Cells; Mice; multidisciplinary; Multigene Family; Regulation; RNA, Messenger - genetics; RNA, Messenger - metabolism; Science; Science (multidisciplinary); Signal transduction; Signaling; Transcription; Transforming Growth Factor beta - metabolism; Transforming growth factor-b
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-19877-5

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. The TGFβ signaling pathway has been shown to regulate transcription by regulating enhancer activity. Here, the authors perform a comprehensive analysis of enhancers in normal mammary epithelial gland cells to elucidate how TGFβ-dependent enhancers control gene transcription in these cells.