Paternal allelic mutation at theKcnq1locus reduces pancreatic β-cell mass by epigenetic modification ofCdkn1c

Genetic factors are important determinants of the onset and progression of diabetes mellitus. Numerous susceptibility genes for type 2 diabetes, including potassium voltage-gated channel, KQT-like subfamily Q, member1 (KCNQ1), have been identified in humans by genome-wide analyses and other studies. Experiments with genetically modified mice have also implicated various genes in the pathogenesis of diabetes. However, the possible effects of the parent of origin for diabetes susceptibility alleles on disease onset have remained unclear. Here, we show that a mutation at theKcnq1locus reduces pancreatic β-cell mass in mice by epigenetic modulation only when it is inherited from the father. The noncoding RNAKCNQ1overlapping transcript1 (Kcnq1ot1) is expressed from theKcnq1locus and regulates the expression of neighboring genes on the paternal allele. We found that disruption ofKcnq1results in reducedKcnq1ot1expression as well as the increased expression of cyclin-dependent kinase inhibitor 1C (Cdkn1c), an imprinted gene that encodes a cell cycle inhibitor, only when the mutation is on the paternal allele. Furthermore, histone modification at theCdkn1cpromoter region in pancreatic islets was found to contribute to this phenomenon. Our observations suggest that theKcnq1genomic region directly regulates pancreatic β-cell mass and that genomic imprinting may be a determinant of the onset of diabetes mellitus.