title: In vitro scan for enhancers at the TCF7L2 locus.
abstract: OBJECTIVE
  Recent functional characterisations of genome-wide association study (GWAS) loci suggest that cis-regulatory variation may be a common paradigm for complex disease susceptibility. Several studies point to a similar mechanism at the transcription factor 7-like 2 (TCF7L2) GWAS locus for type 2 diabetes. To address this possibility, we carried out an in vitro scan of this diabetes-associated locus to fine-map cis-regulatory sequences within this genomic interval.
  
  
  METHODS
  A systematic cell-based enhancer strategy was employed to interrogate all sequences within the 92 kb type-2-diabetes-association interval for cis-regulatory activity in a panel of cell lines (HCT-116, Neuro-2a, C2C12, U2OS, MIN6 and HepG2). We further evaluated chromatin state at a subset of these regions in HCT-116 and U2OS cells and examined allelic-specific enhancer properties at the type-2-diabetes-associated single nucleotide polymorphism (SNP) rs7903146.
  
  
  RESULTS
  In total, we assigned cis-regulatory activity to approximately 30% (9/28) of constructs tested. Notably, a subset of enhancers was active across multiple cell lines and overlapped with key epigenetic markers suggestive of cis-regulatory sequences. We further replicated the allelic-specific properties for SNP rs7903146 in pancreatic beta cells and additionally demonstrate identical allelic-specific enhancer effects in other cell lines.
  
  
  CONCLUSIONS
  These results provide a detailed map of cis-regulatory elements within the TCF7L2 GWAS locus and support the hypothesis of cis-regulatory variation leading to type 2 diabetes predisposition. The detection of allelic-specific effects for SNP rs7903146 in multiple cell lines further alludes to the likelihood of a peripheral defect in disease aetiology.
authors.affiliation: Department of Human Genetics, University of Chicago, 920 E. 58th St, CLSC 319A, Chicago, IL 60637, USA.
authors.forename: D
authors.initials: D
authors.lastname: Savic
authors.forename: S Y
authors.initials: SY
authors.lastname: Park
authors.forename: K A
authors.initials: KA
authors.lastname: Bailey
authors.forename: G I
authors.initials: GI
authors.lastname: Bell
authors.forename: M A
authors.initials: MA
authors.lastname: Nobrega
mesh_terms: D000483:Alleles; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002460:Cell Line; D042002:Chromatin Assembly and Disassembly; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D051379:Mice; D009928:Organ Specificity; D020641:Polymorphism, Single Nucleotide; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013045:Species Specificity; D058118:Transcription Factor 7-Like 2 Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D011994:Recombinant Proteins; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein