The general aim of our work is to study the role played by epigenetics in the etiology of rare inherited diseases. Epigenetic modifications regulate several biological processes, including gene expression. They provide the cell with a fine and dynamic regulation of gene expression and allow the adaptation of organisms to the environment. An altered epigenetic regulation may lead to human diseases.

We are interested in cystic fibrosis (CF), a monogenic disease that results from the impairment of the CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) protein. CFTR is a chloride channel responsible for ion transport across the plasmic membrane of epithelial cells. The defective protein results in thick, sticky and obstructive mucus. CF patients suffer from recurrent pulmonary infections, permanent inflammation, pancreatic insufficiency and male infertility. Morbidity and mortality are mainly due to the progressive loss of lung function. No clear genotype-phenotype correlations have been established for lung disease in CF patients. Even within the group who carries the homozygous F508del mutation, some patients develop a severe lung disease very early during childhood, others have a mild disease until late in adulthood. The variability in phenotypic expression of homozygous F508del mutation emphasizes the role of genetic background (genes other than CFTR) and environmental exposure. Studies in CF twins have shown that the pancreatic insufficiency correlates well with the patient genotype. Conversely, the severity of the lung disease is variable and equally affected by genetic and environmental factors. Non-inherited factors responsible for the phenotypic variations in CF patients are still unknown.
A major effort is done by our group to determine whether epigenetic factors account for the different pulmonary phenotypes that are observed among CF patients. By combining genomics, epigenomics and bioinformatics we aim:

• to determine whether epigenomic modifications (DNA methylation) account for the yet unexplained individual variability in the course of CF.
• to find predictive epigenetic biomarkers of lung disease useful for the follow-up of CF patients (IBDLR supported project).

• Staff

Albertina DE SARIO (DR2 CNRS + HDR)

Lorena VALDES (Master1, University of Montpellier)

• Keywords: DNA methylation, chromatin, cystic fibrosis, biomarkers, pyrosequencing, RNAseq, bioinformatics, cohort of patients, biobank.


• Access

• Selected publications

Pineau F, Caimmi D, Magalhães M, Fremy E, Mohamed A, Mely L, Leroy S, Murris M, Claustres M, Chiron R, De Sario A. Blood co-expression modules identify potential modifier genes of diabetes and lung function in cystic fibrosis. PLoS One.15(4):e0231285. doi: 10.1371/journal.pone.0231285. eCollection (2020). PMID: 32302349

Scott M, De Sario A. DNA methylation changes in cystic fibrosis: Cause or consequence? Clin Genet. doi: 10.1111/cge.13731. (2020) Review. PMID: 32112395

Magalhaes M., Tost J., Pineau F., Rivals I., Busato F., Alary N., Mely L., Leroy S., Murris M., Caimmi D., Claustres M., Chiron R., De Sario A. Dynamic Changes of DNA Methylation and Pulmonary Disease in Cystic Fibrosis: Lessons from a Monogenic Disease. Epigenomics, 2018 Jul doi: 10.2217/epi-2018-0005. PMID: 30052057

Magalhães M, Rivals I, Claustres M, Varilh J, Thomasset M, Bergougnoux A, Mely L, Leroy S, Corvol H, Guillot L, Murris M, Beyne E, Caimmi D, Vachier I, Chiron R and De Sario A. DNA methylation at modifier genes of lung disease severity is altered in cystic fibrosis. Clinical Epigenetics, Clin Epigenetics. 2017 Feb 14;9:19. doi: 10.1186/s13148-016-0300-8. PMID: 28289476

Bergougnoux A, Claustres M, De Sario A. Nasal epithelial cells: a tool to study DNA methylation in airway diseases. Epigenomics. 2015 Feb;7(1):119-26. doi: 10.2217/epi.14.65. PMID: 25687471

Bergougnoux A, Rivals I, Liquori A, Raynal C, Varilh J, Magalhães M, Perez MJ, Bigi N, Des Georges M, Chiron R, Squalli-Houssaini AS, Claustres M, De Sario A. A balance between activating and repressive histone modifications regulates cystic fibrosis transmembrane conductance regulator (CFTR) expression in vivo. Epigenetics. 2014 Jul;9(7):1007-17. doi: 10.4161/epi.28967. Epub 2014 Apr 29. PMID: 24782114