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.
Pubmed ID: 27693352 RIS Download
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Provides standardized vocabulary of phenotypic abnormalities encountered in human disease. Structured and controlled vocabulary for phenotypic features encountered in human hereditary and other disease. HPO is being developed in collaboration with members of OBO Foundry (Open Biological and Biomedical Ontologies), and logical definitions for HPO terms are being developed using PATO and a number of other ontologies including FMA, GO, ChEBI, and MPATH.
View all literature mentionsCollection of human embryonic and fetal material (Tissue and RNA) ranging from 3 to 20 weeks of development available to the international scientific community. Material can either be sent to registered users or our In House Gene Expression Service (IHGES) can carry out projects on user''''s behalf, providing high quality images and interpretation of gene expression patterns. Gene expression data emerging from HDBR material is added to our gene expression database which is accessible via our HUDSEN (Human Developmental Studies Network) website. A significant proportion of the material has been cytogenetically karyotyped, and normal karyotyped material is provided for research.
View all literature mentionsThis polyclonal targets GATA2 - ChIP Grade
View all literature mentionsThis unknown targets Raised against peptide mapping to N-terminus of sox-10 of human origin
View all literature mentionsThis polyclonal targets β-actin
View all literature mentionsThis polyclonal targets Histone H2A
View all literature mentionsThis polyclonal targets Retinoic Acid Receptor beta
View all literature mentionsThis monoclonal targets Human Ret
View all literature mentionsSoftware tool for transcriptome assembly and differential expression analysis for RNA-Seq. Includes script called cuffmerge that can be used to merge together several Cufflinks assemblies. It also handles running Cuffcompare as well as automatically filtering a number of transfrags that are likely to be artifacts. If the researcher has a reference GTF file, the researcher can provide it to the script to more effectively merge novel isoforms and maximize overall assembly quality.
View all literature mentionsSoftware ultrafast memory efficient tool for aligning sequencing reads. Bowtie is short read aligner.
View all literature mentionsCell line SK-N-SH is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line Neuro-2a is a Cancer cell line with a species of origin Mus musculus
View all literature mentionsThis polyclonal targets GATA2 - ChIP Grade
View all literature mentionsThis polyclonal targets GATA2 - ChIP Grade
View all literature mentionsThis polyclonal targets GATA2 - ChIP Grade
View all literature mentions