Cooperative -Regulatory Elements in Intestinal Cells.

About 8% of the human genome is covered with candidate -regulatory elements (cCREs). Disruptions of CREs, described as "-ruptions" have been identified as being involved in various genetic diseases. Thanks to the development of chromatin conformation study techniques, several long-range cystic fibrosis transmembrane conductance regulator () regulatory elements were identified, but the regulatory mechanisms of the gene have yet to be fully elucidated. The aim of this work is to improve our knowledge of the gene regulation, and to identity factors that could impact the gene expression, and potentially account for the variability of the clinical presentation of cystic fibrosis as well as -related disorders. Here, we apply the robust GWAS3D score to determine which of the introns could be involved in gene regulation. This approach highlights four particular introns of interest. Using reporter gene constructs in intestinal cells, we show that two new introns display strong cooperative effects in intestinal cells. Chromatin immunoprecipitation analyses further demonstrate fixation of transcription factors network. These results provide new insights into our understanding of the gene regulation and allow us to suggest a 3D locus structure in intestinal cells. A better understand of regulation mechanisms of the gene could elucidate cases of patients where the phenotype is not yet explained by the genotype. This would thus help in better diagnosis and therefore better management. These -acting regions may be a therapeutic challenge that could lead to the development of specific molecules capable of modulating gene expression in the future.