Long-range gene regulation links genomic type 2 diabetes and obesity risk regions to HHEX, SOX4, and IRX3.
Genome-wide association studies identified noncoding SNPs associated with type 2 diabetes and obesity in linkage disequilibrium (LD) blocks encompassing HHEX-IDE and introns of CDKAL1 and FTO [Sladek R, et al. (2007) Nature 445:881-885; Steinthorsdottir V, et al. (2007) Nat. Genet 39:770-775; Frayling TM, et al. (2007) Science 316:889-894]. We show that these LD blocks contain highly conserved noncoding elements and overlap with the genomic regulatory blocks of the transcription factor genes HHEX, SOX4, and IRX3. We report that human highly conserved noncoding elements in LD with the risk SNPs drive expression in endoderm or pancreas in transgenic mice and zebrafish. Both HHEX and SOX4 have recently been implicated in pancreas development and the regulation of insulin secretion, but IRX3 had no prior association with pancreatic function or development. Knockdown of its orthologue in zebrafish, irx3a, increased the number of pancreatic ghrelin-producing epsilon cells and decreased the number of insulin-producing beta-cells and glucagon-producing alpha-cells, thereby suggesting a direct link of pancreatic IRX3 function to both obesity and type 2 diabetes.
Ragvin
Anja
A
Department of Clinical Medicine, University of Bergen, N-5020 Bergen, Norway.
Moro
Enrico
E
Fredman
David
D
Navratilova
Pavla
P
Drivenes
Øyvind
Ø
Engström
Pär G
PG
Alonso
M Eva
ME
de la Calle Mustienes
Elisa
E
Gómez Skarmeta
José Luis
JL
Tavares
Maria J
MJ
Casares
Fernando
F
Manzanares
Miguel
M
van Heyningen
Veronica
V
Molven
Anders
A
Njølstad
Pål R
PR
Argenton
Francesco
F
Lenhard
Boris
B
Becker
Thomas S
TS
D000818:Animals; D017124:Conserved Sequence; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000453:epidemiology / Q000235:genetics*; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D055106:Genome-Wide Association Study; D018398:Homeodomain Proteins / Q000235:genetics*; D006706:Homeostasis; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics; D009765:Obesity / Q000235:genetics*; D010179:Pancreas / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D055751:SOXC Transcription Factors / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D015027:Zebrafish / Q000235:genetics
C078492:HHEX protein, human; D018398:Homeodomain Proteins; C501598:IRX3 protein, human; D007328:Insulin; C083431:SOX4 protein, human; D055751:SOXC Transcription Factors; D014157:Transcription Factors