PUBLICATION
Multidimensional chromatin profiling of zebrafish pancreas to uncover and investigate disease-relevant enhancers
- Authors
- Bordeira-Carriço, R., Teixeira, J., Duque, M., Galhardo, M., Ribeiro, D., Acemel, R.D., Firbas, P.N., Tena, J.J., Eufrásio, A., Marques, J., Ferreira, F.J., Freitas, T., Carneiro, F., Goméz-Skarmeta, J.L., Bessa, J.
- ID
- ZDB-PUB-220413-19
- Date
- 2022
- Source
- Nature communications 13: 1945 (Journal)
- Registered Authors
- Bessa, Jose, Duque, Marta, Eufrásio, Ana, Ferreira, Fábio, Galhardo, Mafalda, Gómez-Skarmeta, José Luis, Marques, Joana, Teixeira, Joana, Tena, Juan
- Keywords
- none
- MeSH Terms
-
- Animals
- Chromatin/genetics
- Enhancer Elements, Genetic*/genetics
- Genome-Wide Association Study
- Pancreas
- Zebrafish*/genetics
- PubMed
- 35410466 Full text @ Nat. Commun.
Citation
Bordeira-Carriço, R., Teixeira, J., Duque, M., Galhardo, M., Ribeiro, D., Acemel, R.D., Firbas, P.N., Tena, J.J., Eufrásio, A., Marques, J., Ferreira, F.J., Freitas, T., Carneiro, F., Goméz-Skarmeta, J.L., Bessa, J. (2022) Multidimensional chromatin profiling of zebrafish pancreas to uncover and investigate disease-relevant enhancers. Nature communications. 13:1945.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping