The transcriptional regulatory networks that specify and maintain human tissue diversity are largely uncharted. To gain insight into this circuitry, we used chromatin immunoprecipitation combined with promoter microarrays to identify systematically the genes occupied by the transcriptional regulators HNF1alpha, HNF4alpha, and HNF6, together with RNA polymerase II, in human liver and pancreatic islets. We identified tissue-specific regulatory circuits formed by HNF1alpha, HNF4alpha, and HNF6 with other transcription factors, revealing how these factors function as master regulators of hepatocyte and islet transcription. Our results suggest how misregulation of HNF4alpha can contribute to type 2 diabetes.
Type 2 or non-insulin-dependent diabetes mellitus (NIDDM) is the most common form of diabetes worldwide, affecting approximately 4% of the world's adult population. It is multifactorial in origin with both genetic and environmental factors contributing to its development. A genome-wide screen for type 2 diabetes genes carried out in Mexican Americans localized a susceptibility gene, designated NIDDM1, to chromosome 2. Here we describe the positional cloning of a gene located in the NIDDM1 region that shows association with type 2 diabetes in Mexican Americans and a Northern European population from the Botnia region of Finland. This putative diabetes-susceptibility gene encodes a ubiquitously expressed member of the calpain-like cysteine protease family, calpain-10 (CAPN10). This finding suggests a novel pathway that may contribute to the development of type 2 diabetes.
The genetic architecture of common traits, including the number,
frequency, and effect sizes of inherited variants that contribute to individual
risk, has been long debated. Genome-wide association studies have identified
scores of common variants associated with type 2 diabetes, but in aggregate,
these explain only a fraction of heritability. To test the hypothesis that
lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES
consortia performed whole genome sequencing in 2,657 Europeans with and without
diabetes, and exome sequencing in a total of 12,940 subjects from five ancestral
groups. To increase statistical power, we expanded sample size via genotyping
and imputation in a further 111,548 subjects. Variants associated with type 2
diabetes after sequencing were overwhelmingly common and most fell within
regions previously identified by genome-wide association studies. Comprehensive
enumeration of sequence variation is necessary to identify functional alleles
that provide important clues to disease pathophysiology, but large-scale
sequencing does not support a major role for lower-frequency variants in
predisposition to type 2 diabetes.
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