HLA-G gene repression is reversed by demethylation.
The HLA-G molecule plays an important role in immune tolerance, protecting the fetus from maternal immune attack, and probably contributes to graft tolerance and tumor escape from the host immune system. HLA-G expression is tightly regulated and involves mechanisms acting in part at the transcriptional level. Nevertheless, almost all regulatory sequences that govern constitutive and inducible HLA class I gene transcription are disrupted in the HLA-G gene promoter, suggesting an unusual regulatory process. In further investigating the molecular mechanisms of HLA-G gene activation, we evaluated the influence of epigenetic mechanisms on seven HLA-G-negative cell lines that exhibit various phenotypes. Exposure of cells to histone deacetylase inhibitors, or to the demethylating agent 5-aza-2'-deoxycytidine, revealed that HLA-G gene transcription is inhibited by DNA methylation. Reversal of methylation-mediated repression may directly induce HLA-G cell-surface expression, supporting the idea that HLA-G might be activated by such a mechanism during malignancy, inflammation, and allogenic reactions.
Moreau
Philippe
P
Commissariat à l'Energie Atomique, Service de Recherche en Hémato-Immunologie, Direction des Sciences du Vivant/Department de Recherche Médicale, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, 75010 Paris, France. moreau@dsvidf.cea.fr
Mouillot
Gael
G
Rousseau
Philippe
P
Marcou
Celine
C
Dausset
Jean
J
Carosella
Edgardo D
ED
D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015139:Blotting, Southern; D015153:Blotting, Western; D019175:DNA Methylation; D000077209:Decitabine; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D006680:HLA Antigens / Q000096:biosynthesis* / Q000235:genetics*; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis* / Q000235:genetics*; D006655:Histone Deacetylases / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D006680:HLA Antigens; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I; D000077209:Decitabine; D006655:Histone Deacetylases; D001374:Azacitidine