Enhancer Variants Synergistically Drive Dysfunction of a Gene Regulatory Network In Hirschsprung Disease.
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.
Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Sumantra
S
Chatterjee
Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Ashish
A
Kapoor
Genomics Division, MS 84-171, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
Jennifer A
JA
Akiyama
Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Dallas R
DR
Auer
Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Dongwon
D
Lee
Broad Institute, Cambridge, MA 02142, USA.
Stacey
S
Gabriel
Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Courtney
C
Berrios
Genomics Division, MS 84-171, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; U.S. Department of Energy Joint Genome Institute, Walnut Creek, CA 94598, USA.
Len A
LA
Pennacchio
Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: aravinda@jhmi.edu.
Aravinda
A
Chakravarti
D000483:Alleles; D000818:Animals; D001665:Binding Sites; D004195:Disease Models, Animal; D004742:Enhancer Elements, Genetic; D050989:GATA2 Transcription Factor / Q000235:genetics / Q000378:metabolism; D041981:Gastrointestinal Tract / Q000196:embryology; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006627:Hirschsprung Disease / Q000235:genetics*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D022661:RNA, Untranslated / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D055757:SOXE Transcription Factors / Q000235:genetics / Q000378:metabolism
D050989:GATA2 Transcription Factor; C494711:GATA2 protein, human; D022661:RNA, Untranslated; D018168:Receptors, Retinoic Acid; C527923:SOX10 protein, human; D055757:SOXE Transcription Factors; C082925:retinoic acid receptor beta; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human
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