TY - JOUR
T1 - Enhancer Variants Synergistically Drive Dysfunction of a Gene Regulatory Network In Hirschsprung Disease
AU - Chatterjee, Sumantra
AU - Kapoor, Ashish
AU - Akiyama, Jennifer A.
AU - Auer, Dallas R.
AU - Lee, Dongwon
AU - Gabriel, Stacey
AU - Berrios, Courtney
AU - Pennacchio, Len A.
AU - Chakravarti, Aravinda
N1 - Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016/10/6
Y1 - 2016/10/6
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cell.2016.09.005
DO - 10.1016/j.cell.2016.09.005
M3 - Article
C2 - 27693352
AN - SCOPUS:84990831632
SN - 0092-8674
VL - 167
SP - 355-368.e10
JO - Cell
JF - Cell
IS - 2
ER -