Functional characteristics of novel pancreatic Pax6 regulatory elements

Adam Buckle, Ryu-suke Nozawa, Dirk A Kleinjan, Nick Gilbert

Research output: Contribution to journalArticlepeer-review


Complex diseases, such as diabetes, are influenced by comprehensive transcriptional networks. Genome-wide association studies have revealed that variants located in regulatory elements for pancreatic transcription factors are linked to diabetes, including those functionally linked to the paired box transcription factor, Pax6. Pax6 deletions in adult mice cause rapid onset of classic diabetes, but the full spectrum of pancreatic Pax6 regulators is unknown. Using a regulatory element discovery approach we identified two novel Pax6 pancreatic cis-regulatory elements in a poorly characterised regulatory desert. Both new elements, PE3 and PE4, are located 50 and 100 kb upstream, interact with different parts of the Pax6 promoter and nearby non-coding RNAs. They drive expression in the developing pancreas and brain, and code for multiple pancreas related transcription factor binding sites. PE3 binds CTCF and is marked by stem cell identity markers in embryonic stem cells, whilst a common variant located in the PE4 element affects binding of Pax4, a known pancreatic regulatory, altering Pax6 gene expression. To determine the ability of these elements to regulate gene expression synthetic transcriptional activators and repressors were targeted to PE3 and PE4, modulating Pax6 gene expression, as well as influencing neighbouring genes and lncRNAs, implicating the Pax6 locus in pancreas function and diabetes.

Original languageEnglish
Pages (from-to)3434–3448
Number of pages15
JournalHuman Molecular Genetics
Issue number19
Early online date10 Aug 2018
Publication statusPublished - 1 Oct 2018


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