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

• Main Authors: Acemel, R.D (Author), Bessa, J. (Author), Bordeira-Carriço, R. (Author), Carneiro, F. (Author), Duque, M. (Author), Eufrásio, A. (Author), Ferreira, F.J (Author), Firbas, P.N (Author), Freitas, T. (Author), Galhardo, M. (Author), Goméz-Skarmeta, J.L (Author), Marques, J. (Author), Ribeiro, D. (Author), Teixeira, J. (Author), Tena, J.J (Author)
• Format: Article
• Language: English
• Published: Nature Research 2022
• Subjects: animal; Animals; chromatin; Chromatin; Enhancer Elements, Genetic; enhancer region; genetics; genome-wide association study; Genome-Wide Association Study; pancreas; Pancreas; zebra fish; Zebrafish
• Online Access: View Fulltext in Publisher

 The pancreas is a central organ for human diseases. Most alleles uncovered by genome-wide association studies of pancreatic dysfunction traits overlap with non-coding sequences of DNA. Many contain epigenetic marks of cis-regulatory elements 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 cis-regulatory elements faces fundamental challenges, including lack of sequence conservation. Here we combine epigenetic assays with reporter assays in zebrafish and human pancreatic cells to identify interspecies functionally equivalent cis-regulatory elements, regardless of sequence conservation. Among other potential disease-relevant enhancers, we identify a zebrafish ptf1a distal-enhancer whose deletion causes pancreatic agenesis, a phenotype previously found to be induced by mutations in a distal-enhancer of PTF1A in humans, further supporting the causality of this condition in vivo. This approach helps to uncover interspecies functionally equivalent cis-regulatory elements and their potential role in human disease. © 2022, The Author(s).