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Transcriptional control of the progesterone receptor gene by estrogen is a complex mechanism. It involves estrogen receptora 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 pro-gesterone receptor gene expression. | ijFEBS Journal The histone demethylase JARID1A regulates progesterone receptor expression Antje Stratmann1 2 and Bernard Haendler1 1 Therapeutic Research Group Oncology Bayer Schering Pharma AG Berlin Germany 2 Institute of Chemistry and Biochemistry Free University Berlin Germany Keywords ChIP estrogen histone demethylation JARID1 progesterone receptor Correspondence B. Haendler Therapeutic Research Group Oncology Bayer Schering Pharma AG Mullerstr. 178 D-13342 Berlin Germany Fax 49 30 468 18069 Tel 49 40 468 12669 E-mail bernard.haendler@bayer.com Received 12 October 2010 revised 21 January 2011 accepted 21 February 2011 doi 10.1111 j.1742-4658.2011.08058.x Transcriptional control of the progesterone receptor gene by estrogen is a complex mechanism. It involves estrogen receptor a 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 halfsite 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 a 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. .
