title: Histone methylation-dependent mechanisms impose ligand dependency for gene activation by nuclear receptors.
abstract: Nuclear receptors undergo ligand-dependent conformational changes that are required for corepressor-coactivator exchange, but whether there is an actual requirement for specific epigenetic landmarks to impose ligand dependency for gene activation remains unknown. Here we report an unexpected and general strategy that is based on the requirement for specific cohorts of inhibitory histone methyltransferases (HMTs) to impose gene-specific gatekeeper functions that prevent unliganded nuclear receptors and other classes of regulated transcription factors from binding to their target gene promoters and causing constitutive gene activation in the absence of stimulating signals. This strategy, based at least in part on an HMT-dependent inhibitory histone code, imposes a requirement for specific histone demethylases, including LSD1, to permit ligand- and signal-dependent activation of regulated gene expression. These events link an inhibitory methylation component of the histone code to a broadly used strategy that circumvents pathological constitutive gene induction by physiologically regulated transcription factors.
authors.affiliation: Howard Hughes Medical Institute, Department of Molecular Medicine, University of California, San Diego, School of Medicine 9500 Gilman Drive, La Jolla, CA 92093-0648.
authors.forename: Ivan
authors.initials: I
authors.lastname: Garcia-Bassets
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, School of Medicine 9500 Gilman Drive, La Jolla, CA 92093-0648.
authors.forename: Young-Soo
authors.initials: YS
authors.lastname: Kwon
authors.affiliation: Howard Hughes Medical Institute, Department of Molecular Medicine, University of California, San Diego, School of Medicine 9500 Gilman Drive, La Jolla, CA 92093-0648.
authors.forename: Francesca
authors.initials: F
authors.lastname: Telese
authors.affiliation: Howard Hughes Medical Institute, Department of Molecular Medicine, University of California, San Diego, School of Medicine 9500 Gilman Drive, La Jolla, CA 92093-0648.
authors.forename: Gratien G
authors.initials: GG
authors.lastname: Prefontaine
authors.affiliation: Howard Hughes Medical Institute, Department of Molecular Medicine, University of California, San Diego, School of Medicine 9500 Gilman Drive, La Jolla, CA 92093-0648.
authors.forename: Kasey R
authors.initials: KR
authors.lastname: Hutt
authors.affiliation: Howard Hughes Medical Institute, Department of Molecular Medicine, University of California, San Diego, School of Medicine 9500 Gilman Drive, La Jolla, CA 92093-0648.
authors.forename: Christine S
authors.initials: CS
authors.lastname: Cheng
authors.affiliation: Howard Hughes Medical Institute, Department of Molecular Medicine, University of California, San Diego, School of Medicine 9500 Gilman Drive, La Jolla, CA 92093-0648.
authors.forename: Bong-Gun
authors.initials: BG
authors.lastname: Ju
authors.affiliation: Howard Hughes Medical Institute, Department of Molecular Medicine, University of California, San Diego, School of Medicine 9500 Gilman Drive, La Jolla, CA 92093-0648.
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Ohgi
authors.affiliation: Howard Hughes Medical Institute, Department of Molecular Medicine, University of California, San Diego, School of Medicine 9500 Gilman Drive, La Jolla, CA 92093-0648.
authors.forename: Jianxun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, School of Medicine 9500 Gilman Drive, La Jolla, CA 92093-0648.
authors.forename: Laure
authors.initials: L
authors.lastname: Escoubet-Lozach
authors.affiliation: Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, School of Medicine 9500 Gilman Drive, La Jolla, CA 92093-0648.
authors.forename: David W
authors.initials: DW
authors.lastname: Rose
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, School of Medicine 9500 Gilman Drive, La Jolla, CA 92093-0648.
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Glass
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, School of Medicine 9500 Gilman Drive, La Jolla, CA 92093-0648.
authors.forename: Xiang-Dong
authors.initials: XD
authors.lastname: Fu
authors.affiliation: Howard Hughes Medical Institute, Department of Molecular Medicine, University of California, San Diego, School of Medicine 9500 Gilman Drive, La Jolla, CA 92093-0648.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Rosenfeld
mesh_terms: D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D004958:Estradiol / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005786:Gene Expression Regulation; D015894:Genome, Human; D042421:Histone Code; D056466:Histone Demethylases; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008745:Methylation; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D015533:Transcriptional Activation
chemical_list: D047628:Estrogen Receptor alpha; D006657:Histones; D008024:Ligands; D004958:Estradiol; D056466:Histone Demethylases; C495195:KDM1A protein, human; D010089:Oxidoreductases, N-Demethylating; D011495:Histone-Lysine N-Methyltransferase