A balance between activating and repressive histone modifications regulates cystic fibrosis transmembrane conductance regulator (CFTR) expression in vivo.
The 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.
INSERM U827; Montpellier, France; Université Montpellier 1; Montpellier, France; CHU Montpellier; Montpellier, France.
Anne
A
Bergougnoux
Equipe de Statistique Appliquée; ESPCI ParisTech; Paris, France.
Isabelle
I
Rivals
INSERM U827; Montpellier, France; Université Montpellier 1; Montpellier, France.
Alessandro
A
Liquori
INSERM U827; Montpellier, France; Université Montpellier 1; Montpellier, France; CHU Montpellier; Montpellier, France.
Caroline
C
Raynal
INSERM U827; Montpellier, France; Université Montpellier 1; Montpellier, France; CHU Montpellier; Montpellier, France.
Jessica
J
Varilh
INSERM U827; Montpellier, France; Université Montpellier 1; Montpellier, France.
Milena
M
Magalhães
CHU Montpellier; Montpellier, France.
Marie-José
MJ
Perez
CHU Montpellier; Montpellier, France.
Nicole
N
Bigi
INSERM U827; Montpellier, France; Université Montpellier 1; Montpellier, France; CHU Montpellier; Montpellier, France.
Marie
M
Des Georges
CHU Montpellier; Montpellier, France.
Raphaël
R
Chiron
INSERM U827; Montpellier, France; Université Montpellier 1; Montpellier, France.
Ahmed Saad
AS
Squalli-Houssaini
INSERM U827; Montpellier, France; Université Montpellier 1; Montpellier, France; CHU Montpellier; Montpellier, France.
Mireille
M
Claustres
INSERM U827; Montpellier, France; Université Montpellier 1; Montpellier, France.
Albertina
A
De Sario
D000107:Acetylation; D001773:Blood Cells / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D019175:DNA Methylation; D004064:Digestive System / Q000378:metabolism; D005260:Female; D005333:Fetus / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008168:Lung / Q000378:metabolism; D008297:Male; D011247:Pregnancy; D011499:Protein Processing, Post-Translational; D020218:Response Elements
D006657:Histones; D019005:Cystic Fibrosis Transmembrane Conductance Regulator
DNA methylation; bivalent chromatin; cystic fibrosis; enhancers; fetal tissues; histone modifications; promoter