Enhancer-promoter interactions can bypass CTCF-mediated boundaries and contribute to phenotypic robustness.

Autor: Chakraborty S; Unit on Genome Structure and Regulation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA., Kopitchinski N; Unit on Genome Structure and Regulation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA., Zuo Z; Unit on Genome Structure and Regulation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA., Eraso A; Unit on Genome Structure and Regulation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA., Awasthi P; Laboratory Animal Sciences Program, Frederick National Lab for Cancer Research, Frederick, MD, USA., Chari R; Laboratory Animal Sciences Program, Frederick National Lab for Cancer Research, Frederick, MD, USA., Mitra A; Bioinformatics and Scientific Programming Core, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA., Tobias IC; Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario, Canada., Moorthy SD; Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario, Canada., Dale RK; Bioinformatics and Scientific Programming Core, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA., Mitchell JA; Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario, Canada., Petros TJ; Unit on Cellular and Molecular Neurodevelopment, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA., Rocha PP; Unit on Genome Structure and Regulation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA. pedrorocha@nih.gov.; National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. pedrorocha@nih.gov.
Jazyk: angličtina
Zdroj: Nature genetics [Nat Genet] 2023 Feb; Vol. 55 (2), pp. 280-290. Date of Electronic Publication: 2023 Jan 30.
DOI: 10.1038/s41588-022-01295-6
Abstrakt: How enhancers activate their distal target promoters remains incompletely understood. Here we dissect how CTCF-mediated loops facilitate and restrict such regulatory interactions. Using an allelic series of mouse mutants, we show that CTCF is neither required for the interaction of the Sox2 gene with distal enhancers, nor for its expression. Insertion of various combinations of CTCF motifs, between Sox2 and its distal enhancers, generated boundaries with varying degrees of insulation that directly correlated with reduced transcriptional output. However, in both epiblast and neural tissues, enhancer contacts and transcriptional induction could not be fully abolished, and insertions failed to disrupt implantation and neurogenesis. In contrast, Sox2 expression was undetectable in the anterior foregut of mutants carrying the strongest boundaries, and these animals fully phenocopied loss of SOX2 in this tissue. We propose that enhancer clusters with a high density of regulatory activity can better overcome physical barriers to maintain faithful gene expression and phenotypic robustness.
(© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
Databáze: MEDLINE
Externí odkaz: