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A balance between activating and repressive histone modifications regulates cystic fibrosis transmembrane conductance regulator (CFTR ) expression in vivo

By Anne Bergougnoux, Isabelle Rivals, Alessandro Liquori, Caroline Raynal, Jessica Varilh, Milena Magalhães, Marie-José Perez, Nicole Bigi, Marie Des Georges, Raphaël Chiron, Ahmed Saad Squalli-Houssaini, Mireille Claustres and Albertina De Sario

Abstract

International audienceThe genetic mechanisms that regulate CFTR, the gene responsible for cystic fibrosis, have been widely investigated in cultured cells. However, mechanisms responsible for tissue-specific and time-specific expression are not completely elucidated in vivo. Through the survey of public databases, we found that the promoter of CFTR was associated with bivalent chromatin in human embryonic stem (ES) cells. In this work, we analyzed fetal (at different stages of pregnancy) and adult tissues and showed that, in digestive and lung tissues, which expressed CFTR, H3K4me3 was maintained in the promoter. Histone acetylation was high in the promoter and in two intronic enhancers, especially in fetal tissues. In contrast, in blood cells, which did not express CFTR, the bivalent chromatin was resolved (the promoter was labeled by the silencing mark H3K27me3). Cis-regulatory sequences were associated with lowly acetylated histones. We also provide evidence that the tissue-specific expression of CFTR is not regulated by dynamic changes of DNA methylation in the promoter. Overall, this work shows that a balance between activating and repressive histone modifications in the promoter and intronic enhancers results in the fine regulation of CFTR expression during development, thereby ensuring tissue specificity

Topics: DNA methylation, bivalent chromatin, cystic fibrosis, enhancers, fetal tissues, histone modifications, promoter, [SDV]Life Sciences [q-bio]
Publisher: Taylor & Francis
Year: 2014
DOI identifier: 10.4161/epi.28967
OAI identifier: oai:HAL:hal-02433787v1
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