Multidimensional chromatin profiling of zebrafish and human pancreas to uncover and validate disease-related enhancers. The Zebrafish Pancreas Regulome

The pancreas is a central organ for human diseases. Most disease-associated alleles overlap with non-coding cis-regulatory elements of DNA, suggesting that alterations in regulatory sequences contribute to pancreatic diseases. However, the interspecies identification of equivalent cis-regulatory elements required for in vivo testing face fundamental challenges, including lack of sequence conservation. In this work, we performed a combined analysis of ATAC-seq, ChIP-seq, 4C-seq and HiChIP-seq data from zebrafish and human pancreatic cells to identify interspecies functionally equivalent cis-regulatory elements, regardless of sequence conservation. To link cis-regulation with the expression of target genes in the pancreas, we additionally integrated in our analysis own and public RNA-seq data from zebrafish pancreatic cell-types. Among several disease-associated sequences, we identified a zebrafish ptf1a distal enhancer whose deletion generates pancreatic agenesis, demonstrating the causality of this condition in humans. Our results further demonstrate that this phenotype is a consequence of loss of pancreas progenitor cells. Overall, we show that chromatin profiling can uncover interspecies functional equivalency of cis-regulatory elements, contributing to the prediction of new disease-causative enhancers and their role in human disease.