Genomic context sensitivity of insulator function.

Autor:	Ribeiro-Dos-Santos AM; Institute for Systems Genetics, NYU Grossman School of Medicine, New York, New York 10016, USA., Hogan MS; Institute for Systems Genetics, NYU Grossman School of Medicine, New York, New York 10016, USA., Luther RD; Institute for Systems Genetics, NYU Grossman School of Medicine, New York, New York 10016, USA., Brosh R; Institute for Systems Genetics, NYU Grossman School of Medicine, New York, New York 10016, USA., Maurano MT; Institute for Systems Genetics, NYU Grossman School of Medicine, New York, New York 10016, USA.; Department of Pathology, NYU Grossman School of Medicine, New York, New York 10016, USA.
Jazyk:	angličtina
Zdroj:	Genome research [Genome Res] 2022 Mar; Vol. 32 (3), pp. 425-436. Date of Electronic Publication: 2022 Jan 26.
DOI:	10.1101/gr.276449.121
Abstrakt:	The specificity of interactions between genomic regulatory elements and potential target genes is influenced by the binding of insulator proteins such as CTCF, which can act as potent enhancer blockers when interposed between an enhancer and a promoter in a reporter assay. But not all CTCF sites genome-wide function as insulator elements, depending on cellular and genomic context. To dissect the influence of genomic context on enhancer blocker activity, we integrated reporter constructs with promoter-only, promoter and enhancer, and enhancer blocker configurations at hundreds of thousands of genomic sites using the Sleeping Beauty transposase. Deconvolution of reporter activity by genomic position reveals distinct expression patterns subject to genomic context, including a compartment of enhancer blocker reporter integrations with robust expression. The high density of integration sites permits quantitative delineation of characteristic genomic context sensitivity profiles and their decomposition into sensitivity to both local and distant DNase I hypersensitive sites. Furthermore, using a single-cell expression approach to test the effect of integrated reporters for differential expression of nearby endogenous genes reveals that CTCF insulator elements do not completely abrogate reporter effects on endogenous gene expression. Collectively, our results lend new insight into genomic regulatory compartmentalization and its influence on the determinants of promoter-enhancer specificity. (© 2022 Ribeiro-dos-Santos et al.; Published by Cold Spring Harbor Laboratory Press.)
Databáze:	MEDLINE
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