Communication à un colloque
Résumé : Histone methylation plays key roles in the regulation of chromatin structure and function. The recent identification of enzymes that antagonize or remove histone methylation offers new opportunities to appreciate histone methylation plasticity in the regulation of epigenetic pathways. Peptidylarginine deiminase 4 (PADI4) was the first enzyme shown to antagonize histone methylation. PADI4 functions as a histone deiminase converting a methylarginine residue to citrulline at specific sites on the tail of histones H3 and H4. This activity is linked to repression of the estrogen-regulated pS2 promoter. Very little is known as to how PADI4 silences gene expression. To investigate the mechanisms by which histone demethylation and in particular PADI4 functions, and as no PADI4 interactors have been described so far, in vitro interaction assays and coimmunoprecipitations were performed. We found that the histone deacetylase HDAC1 interacts with PADI4, both in vitro and in vivo, and associates with PADI4-mediated histone deiminase activity. Chromatin immunoprecipitations in MDA-ER66 cells using antibodies against PADI4, HDAC1, citrulline H3 and acetylated histones show that PADI4 and HDAC1 appear transiently and in a cyclic manner on the estrogen-responsive promoter pS2, in the presence of estradiol. Their presence correlates with the loss of arginine methylation, acquisition of citrulline, histone deacetylation, and disengagement of RNA polymerase II from the pS2 promoter. Furthermore, sequential ChIP further indicated that PADI4 and HDAC1 bind together to the pS2 promoter in the presence of estrogen. These results further substantiate the “transcriptional clock” concept, highlighting the dynamic interplay between deimination and deacetylation of histones.