Multidimensional chromatin profiling of zebrafish pancreas to uncover and investigate disease-relevant enhancers

Most alleles uncovered by genome-wide association studies of pancreatic dysfunctions overlap with non-coding sequences, many of them, containing epigenetic marks of cis-regulatory elements (CREs) active in pancreatic cells, suggesting that alterations in these sequences contribute to pancreatic diseases. Animal models greatly help to understand the role of non-coding alterations in disease. However, interspecies identification of equivalent CREs faces fundamental challenges, including lack of sequence conservation. A team led by José Bessa from at the i3S, combined epigenetic assays with reporter assays in zebrafish and human pancreatic cells to identify interspecies functionally equivalent CREs, regardless of sequence conservation. Among other potential disease-relevant enhancers, they identified a zebrafish ptf1a distal-enhancer whose deletion causes pancreatic agenesis, a phenotype previously described in humans. This approach helps to uncover interspecies functionally equivalent CREs and their potential role in human disease. The paper entitled "Multidimensional chromatin profiling of zebrafish pancreas to uncover and investigate disease-relevant enhancers" was published in Nature Communications.