Referenced in: none

Automatically associated channels: Kv7.1

Title: Paternal allelic mutation at the Kcnq1 locus reduces pancreatic β-cell mass by epigenetic modification of Cdkn1c.

Authors: Shun-ichiro Asahara, Hiroaki Etoh, Hiroyuki Inoue, Kyoko Teruyama, Yuki Shibutani, Yuka Ihara, Yukina Kawada, Alberto Bartolome, Naoko Hashimoto, Tomokazu Matsuda, Maki Koyanagi-Kimura, Ayumi Kanno, Yushi Hirota, Tetsuya Hosooka, Kazuaki Nagashima, Wataru Nishimura, Hiroshi Inoue, Michihiro Matsumoto, Michael J Higgins, Kazuki Yasuda, Nobuya Inagaki, Susumu Seino, Masato Kasuga, Yoshiaki Kido

Journal, date & volume: Proc. Natl. Acad. Sci. U.S.A., 2015 Jul 7 , 112, 8332-7

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/26100882

Abstract
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 the Kcnq1 locus reduces pancreatic β-cell mass in mice by epigenetic modulation only when it is inherited from the father. The noncoding RNA KCNQ1 overlapping transcript1 (Kcnq1ot1) is expressed from the Kcnq1 locus and regulates the expression of neighboring genes on the paternal allele. We found that disruption of Kcnq1 results in reduced Kcnq1ot1 expression 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 the Cdkn1c promoter region in pancreatic islets was found to contribute to this phenomenon. Our observations suggest that the Kcnq1 genomic region directly regulates pancreatic β-cell mass and that genomic imprinting may be a determinant of the onset of diabetes mellitus.