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

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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
    Heidelberg University)

  • 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)

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.

Suggested Citation

  • Jose A. Guerrero-Martínez & María Ceballos-Chávez & Florian Koehler & Sandra Peiró & Jose C. Reyes, 2020. "TGFβ promotes widespread enhancer chromatin opening and operates on genomic regulatory domains," Nature Communications, Nature, vol. 11(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-19877-5
    DOI: 10.1038/s41467-020-19877-5
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