Characterization of GJB2 cis -regulatory elements in the DFNB1 locus

AbstractAlthough most disease-causing variants are within coding region of genes, it is now well established thatcis-acting regulatory sequences, depending on 3D-chromatin organization, are required for temporal and spatial control of gene expression. Disruptions of such regulatory elements and/or chromatin conformation are likely to play a critical role in human genetic disease. Hence, recurrent monoallelic cases, who present the most common hereditary type of nonsyndromic hearing loss (i.e.,DFNB1), carry only one identified pathogenic allele. This strongly suggests the presence of uncharacterized distalcis-acting elements in the missing allele. Here within, we study the spatial organization of a largeDFNB1 locus encompassing the gap junction protein beta 2 (GJB2) gene, the most frequently mutated gene in this inherited hearing loss phenotype, with the chromosome conformation capture carbon copy technology (5C). By combining this approach with functional activity reporter assays and mapping of CCCTC-binding factor (CTCF) along theDFNB1 locus, we identify a novel set of cooperatingGJB2 cis-acting elements and suggest aDFNB1 three-dimensional looping regulation model.

Source: Human Genetics - October 3, 2019 Category: Genetics & Stem Cells Source Type: research