Enhancer Variants Synergistically Drive Dysfunction of a Gene Regulatory Network In Hirschsprung Disease.

Cell
Authors
Keywords
Abstract

Common sequence variants in cis-regulatory elements (CREs) are suspected etiological causes of complex disorders. We previously identified an intronic enhancer variant in the RET gene disrupting SOX10 binding and increasing Hirschsprung disease (HSCR) risk 4-fold. We now show that two other functionally independent CRE variants, one binding Gata2 and the other binding Rarb, also reduce Ret expression and increase risk 2- and 1.7-fold. By studying human and mouse fetal gut tissues and cell lines, we demonstrate that reduced RET expression propagates throughout its gene regulatory network, exerting effects on both its positive and negative feedback components. We also provide evidence that the presence of a combination of CRE variants synergistically reduces RET expression and its effects throughout the GRN. These studies show how the effects of functionally independent non-coding variants in a coordinated gene regulatory network amplify their individually small effects, providing a model for complex disorders.

Year of Publication
2016
Journal
Cell
Volume
167
Issue
2
Pages
355-368.e10
Date Published
2016 Oct 06
ISSN
1097-4172
DOI
10.1016/j.cell.2016.09.005
PubMed ID
27693352
PubMed Central ID
PMC5113733
Links
Grant list
R01 HG003988 / HG / NHGRI NIH HHS / United States
U01 DE020060 / DE / NIDCR NIH HHS / United States
R37 HD028088 / HD / NICHD NIH HHS / United States
R01 HD028088 / HD / NICHD NIH HHS / United States
U54 HG006997 / HG / NHGRI NIH HHS / United States