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

Renata Bordeira-Carriço, Joana Teixeira, Marta Duque, Mafalda Galhardo, Diogo Ribeiro, Rafael D. Acemel, Panos. N. Firbas, Juan J. Tena, Ana Eufrásio, Joana Marques, Fábio J. Ferreira, Telmo Freitas, Fátima Carneiro, José Luís Goméz-Skarmeta and José Bessa ()
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Renata Bordeira-Carriço: Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto
Joana Teixeira: Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto
Marta Duque: Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto
Mafalda Galhardo: Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto
Diogo Ribeiro: Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto
Rafael D. Acemel: Centro Andaluz de Biología del Desarrollo (CABD), Universidad Pablo de Olavide
Panos. N. Firbas: Centro Andaluz de Biología del Desarrollo (CABD), Universidad Pablo de Olavide
Juan J. Tena: Centro Andaluz de Biología del Desarrollo (CABD), Universidad Pablo de Olavide
Ana Eufrásio: Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto
Joana Marques: Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto
Fábio J. Ferreira: Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto
Telmo Freitas: Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto
Fátima Carneiro: Faculdade de Medicina da Universidade do Porto (FMUP)
José Luís Goméz-Skarmeta: Centro Andaluz de Biología del Desarrollo (CABD), Universidad Pablo de Olavide
José Bessa: Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: 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.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29551-7

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DOI: 10.1038/s41467-022-29551-7

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