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

• Type: Article in International Scientific Journal
• Date: 2022

Authors

Bordeira-Carrico, R (Author) Other; Teixeira, J (Author) Other; Duque, M (Author) Other; Galhardo, M (Author) Other; Ribeiro, D (Author) Other; Acemel, RD (Author) Other; Firbas, PN (Author) Other; Tena, JJ (Author) Other; Eufrasio, A (Author) Other; Marques, J (Author) Other; Ferreira, FJ (Author) Other; Freitas, T (Author) Other; Carneiro F (Author) FMUP; Gomez-Skarmeta, JL (Author) Other; Bessa, J (Author) Other

Journal

Title: Nature Communications

Vol. 13

ISSN: 2041-1723

Publisher: Springer Nature

Indexing

ISI Web of Knowledge - 0 Citations

Scopus

Other information

Authenticus ID: P-00W-FK0

DOI: 10.1038/s41467-022-29551-7

Abstract (EN): 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. Alterations in cis-regulatory elements (CREs) can contribute to pancreatic diseases. Here the authors combine chromatin profiling and interaction points with in vivo reporter assays in zebrafish to uncover functionally equivalent human CREs, helping to predict disease-relevant enhancers.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 17