title: Paternal allelic mutation at the Kcnq1 locus reduces pancreatic β-cell mass by epigenetic modification of Cdkn1c.
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.
authors.affiliation: Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Hyogo 650-0017, Japan;
authors.forename: Shun-ichiro
authors.initials: S
authors.lastname: Asahara
authors.affiliation: Division of Medical Chemistry, Department of Biophysics, Kobe University Graduate School of Health Sciences, Hyogo 654-0142, Japan;
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Etoh
authors.affiliation: Division of Medical Chemistry, Department of Biophysics, Kobe University Graduate School of Health Sciences, Hyogo 654-0142, Japan;
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Inoue
authors.affiliation: Division of Medical Chemistry, Department of Biophysics, Kobe University Graduate School of Health Sciences, Hyogo 654-0142, Japan;
authors.forename: Kyoko
authors.initials: K
authors.lastname: Teruyama
authors.affiliation: Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Hyogo 650-0017, Japan;
authors.forename: Yuki
authors.initials: Y
authors.lastname: Shibutani
authors.affiliation: Division of Medical Chemistry, Department of Biophysics, Kobe University Graduate School of Health Sciences, Hyogo 654-0142, Japan;
authors.forename: Yuka
authors.initials: Y
authors.lastname: Ihara
authors.affiliation: Division of Medical Chemistry, Department of Biophysics, Kobe University Graduate School of Health Sciences, Hyogo 654-0142, Japan;
authors.forename: Yukina
authors.initials: Y
authors.lastname: Kawada
authors.affiliation: Division of Medical Chemistry, Department of Biophysics, Kobe University Graduate School of Health Sciences, Hyogo 654-0142, Japan;
authors.forename: Alberto
authors.initials: A
authors.lastname: Bartolome
authors.affiliation: Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Hyogo 650-0017, Japan;
authors.forename: Naoko
authors.initials: N
authors.lastname: Hashimoto
authors.affiliation: Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Hyogo 650-0017, Japan;
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Matsuda
authors.affiliation: Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Hyogo 650-0017, Japan;
authors.forename: Maki
authors.initials: M
authors.lastname: Koyanagi-Kimura
authors.affiliation: Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Hyogo 650-0017, Japan;
authors.forename: Ayumi
authors.initials: A
authors.lastname: Kanno
authors.affiliation: Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Hyogo 650-0017, Japan;
authors.forename: Yushi
authors.initials: Y
authors.lastname: Hirota
authors.affiliation: Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Hyogo 650-0017, Japan;
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Hosooka
authors.affiliation: Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan;
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Nagashima
authors.affiliation: Department of Anatomy, Jichi Medical University, Tochigi 329-0498, Japan;
authors.forename: Wataru
authors.initials: W
authors.lastname: Nishimura
authors.affiliation: Frontier Science Organization, Kanazawa University, Ishikawa 320-8641, Japan;
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Inoue
authors.affiliation: Department of Molecular Metabolic Regulation, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan;
authors.forename: Michihiro
authors.initials: M
authors.lastname: Matsumoto
authors.affiliation: Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY 14263;
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Higgins
authors.affiliation: Department of Metabolic Disorder, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan;
authors.forename: Kazuki
authors.initials: K
authors.lastname: Yasuda
authors.affiliation: Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan;
authors.forename: Nobuya
authors.initials: N
authors.lastname: Inagaki
authors.affiliation: Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Hyogo 650-0017, Japan; Division of Molecular and Metabolic Medicine, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Hyogo 650-0017, Japan;
authors.forename: Susumu
authors.initials: S
authors.lastname: Seino
authors.affiliation: National Center for Global Health and Medicine, Tokyo 162-8655, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Kasuga
authors.affiliation: Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Hyogo 650-0017, Japan; Division of Medical Chemistry, Department of Biophysics, Kobe University Graduate School of Health Sciences, Hyogo 654-0142, Japan; kido@med.kobe-u.ac.jp.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kido
mesh_terms: D000483:Alleles; D000818:Animals; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000235:genetics* / Q000378:metabolism; D044127:Epigenesis, Genetic; D015870:Gene Expression; D018392:Genomic Imprinting / Q000235:genetics; D005947:Glucose / Q000494:pharmacology; D005951:Glucose Tolerance Test; D015151:Immunoblotting; D040582:Inheritance Patterns; D007328:Insulin / Q000097:blood / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D051657:KCNQ1 Potassium Channel / Q000235:genetics* / Q000378:metabolism; D008297:Male; D018345:Mice, Knockout; D009154:Mutation; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C493965:Cdkn1c protein, mouse; D050761:Cyclin-Dependent Kinase Inhibitor p57; D007328:Insulin; D051657:KCNQ1 Potassium Channel; C496910:Kcnq1 protein, mouse; D005947:Glucose
keywords: Kcnq1; imprinting; pancreatic β-cells