A cistrome roadmap for understanding pancreatic islet biology

Abstract

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.

Figure 1

Model of how genetic variants in enhancers of islet-expressed genes contribute to islet cell dysfunction and increased risk of T2D. Top, an allele with an intact transcription factor binding site in an enhancer cluster far distal to the promoter of an islet-expressed gene. Interaction of the enhancer with the promoter leads to high levels of gene transcription. Bottom, a T2D risk allele that disrupts transcription factor binding in the enhancer cluster. The interaction of the enhancer with the promoter is weakened, and transcriptional activity is reduced. Over many decades, reduced levels of the corresponding protein contribute to islet dysfunction.