Role of transcription factor KLF11 and its diabetes-associated gene variants in pancreatic beta cell function

TY - JOUR

T1 - Role of transcription factor KLF11 and its diabetes-associated gene variants in pancreatic beta cell function

AU - Neve, Bernadette

AU - Fernandez-Zapico, Martin E

AU - Ashkenazi-Katalan, Vered

AU - Dina, Christian

AU - Hamid, Yasmin H

AU - Joly, Erik

AU - Vaillant, Emmanuel

AU - Benmezroua, Yamina

AU - Durand, Emmanuelle

AU - Bakaher, Nicolas

AU - Delannoy, Valerie

AU - Vaxillaire, Martine

AU - Cook, Tiffany

AU - Dallinga-Thie, Geesje M

AU - Jansen, Hans

AU - Charles, Marie-Aline

AU - Clément, Karine

AU - Galan, Pilar

AU - Hercberg, Serge

AU - Helbecque, Nicole

AU - Charpentier, Guillaume

AU - Prentki, Marc

AU - Hansen, Torben

AU - Pedersen, Oluf

AU - Urrutia, Raul

AU - Melloul, Danielle

AU - Froguel, Philippe

PY - 2005

Y1 - 2005

N2 - KLF11 (TIEG2) is a pancreas-enriched transcription factor that has elicited significant attention because of its role as negative regulator of exocrine cell growth in vitro and in vivo. However, its functional role in the endocrine pancreas remains to be established. Here, we report, for the first time, to our knowledge, the characterization of KLF11 as a glucose-inducible regulator of the insulin gene. A combination of random oligonucleotide binding, EMSA, luciferase reporter, and chromatin immunoprecipitation assays shows that KLF11 binds to the insulin promoter and regulates its activity in beta cells. Genetic analysis of the KLF11 gene revealed two rare variants (Ala347Ser and Thr220Met) that segregate with diabetes in families with early-onset type 2 diabetes, and significantly impair its transcriptional activity. In addition, analysis of 1,696 type 2 diabetes mellitus and 1,776 normoglycemic subjects show a frequent polymorphic Gln62Arg variant that significantly associates with type 2 diabetes mellitus in North European populations (OR = 1.29, P = 0.00033). Moreover, this variant alters the corepressor mSin3A-binding activity of KLF11, impairs the activation of the insulin promoter and shows lower levels of insulin expression in pancreatic beta cells. In addition, subjects carrying the Gln62Arg allele show decreased plasma insulin after an oral glucose challenge. Interestingly, all three nonsynonymous KLF11 variants show increased repression of the catalase 1 promoter, suggesting a role in free radical clearance that may render beta cells more sensitive to oxidative stress. Thus, both functional and genetic analyses reveal that KLF11 plays a role in the regulation of pancreatic beta cell physiology, and its variants may contribute to the development of diabetes.

AB - KLF11 (TIEG2) is a pancreas-enriched transcription factor that has elicited significant attention because of its role as negative regulator of exocrine cell growth in vitro and in vivo. However, its functional role in the endocrine pancreas remains to be established. Here, we report, for the first time, to our knowledge, the characterization of KLF11 as a glucose-inducible regulator of the insulin gene. A combination of random oligonucleotide binding, EMSA, luciferase reporter, and chromatin immunoprecipitation assays shows that KLF11 binds to the insulin promoter and regulates its activity in beta cells. Genetic analysis of the KLF11 gene revealed two rare variants (Ala347Ser and Thr220Met) that segregate with diabetes in families with early-onset type 2 diabetes, and significantly impair its transcriptional activity. In addition, analysis of 1,696 type 2 diabetes mellitus and 1,776 normoglycemic subjects show a frequent polymorphic Gln62Arg variant that significantly associates with type 2 diabetes mellitus in North European populations (OR = 1.29, P = 0.00033). Moreover, this variant alters the corepressor mSin3A-binding activity of KLF11, impairs the activation of the insulin promoter and shows lower levels of insulin expression in pancreatic beta cells. In addition, subjects carrying the Gln62Arg allele show decreased plasma insulin after an oral glucose challenge. Interestingly, all three nonsynonymous KLF11 variants show increased repression of the catalase 1 promoter, suggesting a role in free radical clearance that may render beta cells more sensitive to oxidative stress. Thus, both functional and genetic analyses reveal that KLF11 plays a role in the regulation of pancreatic beta cell physiology, and its variants may contribute to the development of diabetes.

KW - Base Composition

KW - Base Sequence

KW - Case-Control Studies

KW - Cell Cycle Proteins

KW - Chromatin Immunoprecipitation

KW - Diabetes Mellitus, Type 2

KW - Europe

KW - Gene Components

KW - Gene Expression Regulation

KW - Humans

KW - Insulin

KW - Islets of Langerhans

KW - Luciferases

KW - Molecular Sequence Data

KW - Pedigree

KW - Polymorphism, Genetic

KW - Promoter Regions, Genetic

KW - Repressor Proteins

KW - Sequence Alignment

KW - Sequence Analysis, DNA

KW - Transcription Factors

U2 - 10.1073/pnas.0409177102

DO - 10.1073/pnas.0409177102

M3 - Journal article

C2 - 15774581

SN - 0027-8424

VL - 102

SP - 4807

EP - 4812

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 13

ER -