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A cistrome roadmap for understanding pancreatic islet biology

Nature Genetics volume 46, pages 95–96 (2014)Cite this article

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Although dozens of common variants have been associated with increased risk of type 2 diabetes (T2D), the mechanisms by which these variants increase disease susceptibility are largely unknown. A new study mapping the human pancreatic islet cistrome provides a roadmap for exploring the effects of these variants and suggests that altered enhancer function might be a common contributor to the genetic risk of T2D.

T2D affects over 300 million people worldwide, and its incidence is predicted to double by 2035. Although well-known behavioral factors such as overeating and a sedentary lifestyle are major contributors to the diabetes epidemic, a heritable component has long been recognized to contribute to an individual's risk of becoming diabetic. Large-scale genetic mapping efforts over the past 10 years have identified more than 60 loci encompassing up to 500 genes as contributing to the disease, but the mechanisms by which these variants act are largely unknown1,2,3. On page 136 of this issue, Jorge Ferrer and colleagues4 have laid the groundwork for an improved molecular understanding of these T2D-associated variants and of human islet biology in general. In a truly heroic effort combining the work and expertise of laboratories in five countries, the group mapped the locations of five key transcriptional regulators known to function in hormone-producing cells of the endocrine pancreas and integrated these data with multiple histone marks—indicating transcriptionally active and repressed areas in the genome—and measures of accessible or 'open' chromatin. The resulting human islet 'cistrome', a genome-wide map of chromatin features and transcription factor binding sites, represents a valuable resource that will yield new insights for many years to come.

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Figure 1: Model of how genetic variants in enhancers of islet-expressed genes contribute to islet cell dysfunction and increased risk of T2D.

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Authors and Affiliations

  1. Dana Avrahami and Klaus H. Kaestner are in the Department of Genetics and the Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.,

    Dana Avrahami & Klaus H Kaestner

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  1. Dana Avrahami
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  2. Klaus H Kaestner
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Correspondence to Klaus H Kaestner.

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The authors declare no competing financial interests.

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Avrahami, D., Kaestner, K. A cistrome roadmap for understanding pancreatic islet biology. Nat Genet 46, 95–96 (2014). https://doi.org/10.1038/ng.2880

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