Cooperative insulation of regulatory domains by CTCF-dependent physical insulation and promoter competition

Thais Ealo, Victor Sanchez-Gaya (), Patricia Respuela, María Muñoz-San Martín, Elva Martin-Batista, Endika Haro () and Alvaro Rada-Iglesias ()
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Thais Ealo: Institute of Biomedicine and Biotechnology of Cantabria (IBBTEC), CSIC/Universidad de Cantabria
Victor Sanchez-Gaya: Institute of Biomedicine and Biotechnology of Cantabria (IBBTEC), CSIC/Universidad de Cantabria
Patricia Respuela: Institute of Biomedicine and Biotechnology of Cantabria (IBBTEC), CSIC/Universidad de Cantabria
María Muñoz-San Martín: Institute of Biomedicine and Biotechnology of Cantabria (IBBTEC), CSIC/Universidad de Cantabria
Elva Martin-Batista: CSIC-UAM
Endika Haro: Institute of Biomedicine and Biotechnology of Cantabria (IBBTEC), CSIC/Universidad de Cantabria
Alvaro Rada-Iglesias: Institute of Biomedicine and Biotechnology of Cantabria (IBBTEC), CSIC/Universidad de Cantabria

Nature Communications, 2024, vol. 15, issue 1, 1-22

Abstract: Abstract The specificity of gene expression during development requires the insulation of regulatory domains to avoid inappropriate enhancer-gene interactions. In vertebrates, this insulator function is mostly attributed to clusters of CTCF sites located at topologically associating domain (TAD) boundaries. However, TAD boundaries allow some physical crosstalk across regulatory domains, which is at odds with the specific and precise expression of developmental genes. Here we show that developmental genes and nearby clusters of CTCF sites cooperatively foster the robust insulation of regulatory domains. By genetically dissecting a couple of representative loci in mouse embryonic stem cells, we show that CTCF sites prevent undesirable enhancer-gene contacts (i.e. physical insulation), while developmental genes preferentially contribute to regulatory insulation through non-structural mechanisms involving promoter competition rather than enhancer blocking. Overall, our work provides important insights into the insulation of regulatory domains, which in turn might help interpreting the pathological consequences of certain structural variants.

Date: 2024
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DOI: 10.1038/s41467-024-51602-4

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