Endocrine Abstracts

Gonadotropin releasing hormone actively de-represses expression of the gonadotropin subunit genes through several actions that target the chromatin. We have shown in the past that both LHβ and FSHβ genes are repressed by histone deacetylases (HDACs) in αT3-1 gonadotrope cells and that this repression is overcome by exposure to GnRH which facilitates HDAC removal via CaMKI-mediated phosphorylation. At the LHβ gene promoter, both histone acetylation and phosphorylation increase quite dramatically following GnRH treatment. The H3 lysine four is trimethylated (H3K4me3) at the LHβ gene promoter prior to treatment, while at the FSHβ promoter this modification is increased following GnRH exposure. However at both promoters there is a loss of histone H3 after GnRH treatment, indicating nucleosomal repositioning. H3K4me3 is commonly seen at the promoters of actively transcribed genes, and is recognized by chromo- tudor and PHD domain proteins. It is commonly associated with histone phosphorylation and acetylation and several studies indicate the requirement of all three modifications for transcriptional activation to proceed. The histone acetyl transferase (HAT) GCN5, which is found at the LHβ gene promoter, was shown in other systems to bind preferentially to the phosphorylated H3S10, indicating that the phosphorylation might signal recruitment of the HAT complex to certain genes. Our current working model is that the H3K14ac and pH3S10 are bound by GCN5 which recruits the larger co-activator complex to signal elongation, possibly with the help of additional proteins that recognize specifically the H3K4me3.