A multi-enhancer RET regulatory code is disrupted in Hirschsprung disease.

Autor:	Chatterjee S; Center for Human Genetics and Genomics, New York University Grossman School of Medicine, New York, New York 10016, USA.; Department of Neuroscience and Physiology, New York University Grossman School of Medicine, New York, New York 10016, USA., Karasaki KM; Department of Biology, Johns Hopkins University, Baltimore, Maryland 21205, USA., Fries LE; Center for Human Genetics and Genomics, New York University Grossman School of Medicine, New York, New York 10016, USA., Kapoor A; Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA., Chakravarti A; Center for Human Genetics and Genomics, New York University Grossman School of Medicine, New York, New York 10016, USA.; Department of Neuroscience and Physiology, New York University Grossman School of Medicine, New York, New York 10016, USA.
Jazyk:	angličtina
Zdroj:	Genome research [Genome Res] 2021 Dec; Vol. 31 (12), pp. 2199-2208. Date of Electronic Publication: 2021 Nov 15.
DOI:	10.1101/gr.275667.121
Abstrakt:	The major genetic risk factors for Hirschsprung disease (HSCR) are three common polymorphisms within cis -regulatory elements (CREs) of the receptor tyrosine kinase gene RET , which reduce its expression during enteric nervous system (ENS) development. These risk variants attenuate binding of the transcription factors RARB, GATA2, and SOX10 to their cognate CREs, reduce RET gene expression, and dysregulate other ENS and HSCR genes in the RET-EDNRB gene regulatory network (GRN). Here, we use siRNA, ChIP, and CRISPR-Cas9 deletion analyses in the SK-N-SH cell line to ask how many additional HSCR-associated risk variants reside in RET CREs that affect its gene expression. We identify 22 HSCR-associated variants in candidate RET CREs, of which seven have differential allele-specific in vitro enhancer activity, and four of these seven affect RET gene expression; of these, two enhancers are bound by the transcription factor PAX3. We also show that deleting multiple variant-containing enhancers leads to synergistic effects on RET gene expression. These, coupled with our prior results, show that common sequence variants in at least 10 RET enhancers affect HSCR risk, seven with experimental evidence of affecting RET gene expression, extending the known RET-EDNRB GRN to reveal an extensive regulatory code modulating disease risk at a single gene. (© 2021 Chatterjee et al.; Published by Cold Spring Harbor Laboratory Press.)
Databáze:	MEDLINE
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