PUBLICATION

Long-range gene regulation links genomic type 2 diabetes and obesity risk regions to HHEX, SOX4, and IRX3

Authors
Ragvin, A., Moro, E., Fredman, D., Navratilova, P., Drivenes, O., Engström, P.G., Alonso, M.E., Mustienes, E.D., Gomez Skarmeta, J.L., Tavares, M.J., Casares, F., Manzanares, M., van Heyningen, V., Molven, A., Njølstad, P.R., Argenton, F., Lenhard, B., and Becker, T.S.
ID
ZDB-PUB-100119-21
Date
2010
Source
Proceedings of the National Academy of Sciences of the United States of America   107(2): 775-780 (Journal)
Registered Authors
Argenton, Francesco, Becker, Thomas S., Casares, Fernando, de la Calle-Mustienes, Elisa, Drivenes, Oyvind, Gómez-Skarmeta, José Luis, Molven, Anders, Moro, Enrico, Navratilova, Pavla, Tavares, Maria, van Heyningen, Veronica
Keywords
hb9, hlxb9, nkx2.2, pancreatic islet development, pancreatic peptides
MeSH Terms
  • Animals
  • Conserved Sequence
  • Diabetes Mellitus, Type 2/complications
  • Diabetes Mellitus, Type 2/epidemiology
  • Diabetes Mellitus, Type 2/genetics*
  • Gene Expression Regulation*
  • Genes, Reporter
  • Genome-Wide Association Study
  • Homeodomain Proteins/genetics*
  • Homeostasis
  • Humans
  • Insulin
  • Mice
  • Mice, Transgenic/genetics
  • Obesity/genetics*
  • Pancreas/physiology
  • Polymorphism, Single Nucleotide*
  • Risk Factors
  • SOXC Transcription Factors/genetics*
  • Transcription Factors/genetics*
  • Zebrafish/genetics
PubMed
20080751 Full text @ Proc. Natl. Acad. Sci. USA
Abstract
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.
Genes / Markers
Figures
Figure Gallery
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes