The histone demethylase JARID1A regulates progesterone receptor expression

Transcriptional control of the progesterone receptor gene by estrogen is a complex mechanism. It involves estrogen receptor α which uses several enzymes that locally modify histone tails as cofactors. Using MCF-7 cells as a model, we found that Jumonji AT-rich interactive domain 1A (JARID1A; KDM5A/RBP2), an enzyme that removes the activating H3K4 di- and trimethylation marks, was involved in the fine-tuning of progesterone receptor gene expression. Reduction of JARID1A led to enhanced progesterone receptor expression, at both the basal and estrogen-stimulated levels. Conversely, overexpression of JARID1A wild-type, but not the enzymatically inactive mutant, suppressed progesterone receptor promoter activity. Chromatin immunoprecipitation experiments showed JARID1A to bind in a ligand-independent manner to a progesterone receptor gene upstream region that contains an estrogen response element half-site as well as the CCGCCC sequence, which is potentially recognized by JARID1A. Estrogen treatment led to RNA polymerase II recruitment to this region and to increased estrogen receptor α binding to the PR enhancer region 1. In addition, elevation of H3K4 trimethylation was detected at the estrogen response element half-site region. Reduction of JARID1A expression was followed by higher H3K4 trimethylation in this region. Analysis of MDA-MB-231 cells, which do not express the progesterone receptor, indicated that H3K4 trimethylation did not take place in the regulatory regions examined. Taken together, the results underscore the importance of epigenetic modifications for regulation of progesterone receptor expression. They suggest that H3K4 tri- and dimethylation play an important role and that JARID1A is the histone-demethylating enzyme responsible for removal of this mark.