Journal
CELL
Volume 167, Issue 2, Pages 355-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2016.09.005
Keywords
-
Categories
Funding
- NIDCR FaceBase grant [U01DE020060]
- NHGRI [R01HG003988, U54HG006997]
- Department of Energy [DE-AC02-05CH11231]
- Joint MRC/Wellcome Trust Human Developmental Biology Resource [099175/Z/12/Z]
- NIH MERIT Award [HD28088]
- MRC [MC_PC_15004, G0700089] Funding Source: UKRI
- Medical Research Council [G0700089, MC_PC_15004] Funding Source: researchfish
Ask authors/readers for more resources
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
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available