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

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.

Authors:

Chatterjee, Sumantra; Kapoor, Ashish; Akiyama, Jennifer A.; Auer, Dallas R.; Lee, Dongwon; Gabriel, Stacey; Berrios, Courtney; Pennacchio, Len A.; Chakravarti, Aravinda

Publication Date:

Sat Oct 01 00:00:00 EDT 2016

Research Org.:

Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Org.:

USDOE Office of Science (SC)

OSTI Identifier:

1550701

Alternate Identifier(s):

OSTI ID: 1398429

Grant/Contract Number:  

AC02-05CH11231

Resource Type:

Published Article

Journal Name:

Cell

Additional Journal Information:

Journal Name: Cell Journal Volume: 167 Journal Issue: 2; Journal ID: ISSN 0092-8674

Publisher:

Elsevier

Country of Publication:

United States

Language:

English

Subject:

59 BASIC BIOLOGICAL SCIENCES