title: Class I lysine deacetylases promote glucocorticoid-induced transcriptional repression through functional interaction with LSD1.
abstract: Small molecule inhibitors of lysine deacetylases (KDACs) are approved for clinical use in treatment of several diseases. Nuclear receptors, such as the glucocorticoid receptor (GR) use lysine acetyltransferases (KATs or HATs) and KDACs to regulate transcription through acetylation and deacetylation of protein targets such as histones. Previously we have shown that KDAC1 activity facilitates GR-activated transcription at about half of all cellular target genes. In the current study we examine the role of Class I KDACs in glucocorticoid-mediated repression of gene expression. Inhibition of KDACs through two structurally distinct Class I-selective inhibitors prevented dexamethasone (Dex)-mediated transcriptional repression in a gene-selective fashion. In addition, KDAC activity is also necessary to maintain repression. Steroid receptor coactivator 2 (SRC2), which is known to play a vital role in GR-mediated repression of pro-inflammatory genes, was found to be dispensable for repression of glucocorticoid target genes sensitive to KDAC inhibition. At the promoters of these genes, KDAC inhibition did not result in altered nucleosome occupancy or histone H3 acetylation. Surprisingly, KDAC inhibition rapidly induced a significant decrease in H3K4Me2 at promoter nucleosomes with no corresponding change in H3K4Me3, suggesting the activation of the lysine demethylase, LSD1/KDM1A. Depletion of LSD1 expression via siRNA restored Dex-mediated repression in the presence of KDAC inhibitors, suggesting that LSD1 activation at these gene promoters is incompatible with transcriptional repression. Treatment with KDAC inhibitors does not alter cellular levels of LSD1 or its association with Dex-repressed gene promoters. Therefore, we conclude that Class I KDACs facilitate Dex-induced transcriptional repression by suppressing LSD1 complex activity at selected target gene promoters. Rather than facilitating repression of transcription, LSD1 opposes it in these gene contexts.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Arizona, Tucson, AZ, 85721, United States; Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ, 85721, United States.
authors.forename: Nina M
authors.initials: NM
authors.lastname: Patrick
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ, 85721, United States.
authors.forename: Chanel A
authors.initials: CA
authors.lastname: Griggs
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ, 85721, United States.
authors.forename: Ali L
authors.initials: AL
authors.lastname: Icenogle
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ, 85721, United States.
authors.forename: Maryam M
authors.initials: MM
authors.lastname: Gilpatrick
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ, 85721, United States; Department of Chemistry and Biochemistry, College of Science, University of Arizona, Tucson, AZ, 85721, United States.
authors.forename: Vineela
authors.initials: V
authors.lastname: Kadiyala
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ, 85721, United States.
authors.forename: Rosa
authors.initials: R
authors.lastname: Jaime-Frias
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ, 85721, United States. Electronic address: csmith@pharmacy.arizona.edu.
authors.forename: Catharine L
authors.initials: CL
authors.lastname: Smith
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003907:Dexamethasone / Q000737:chemistry; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000378:metabolism*; D006655:Histone Deacetylases / Q000378:metabolism*; D056466:Histone Demethylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D007249:Inflammation; D008239:Lysine / Q000378:metabolism*; D051379:Mice; D051958:Nuclear Receptor Coactivator 2 / Q000378:metabolism; D009707:Nucleosomes / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012313:RNA / Q000032:analysis; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: D005938:Glucocorticoids; D006657:Histones; D051958:Nuclear Receptor Coactivator 2; D009707:Nucleosomes; D034741:RNA, Small Interfering; D012313:RNA; D003907:Dexamethasone; D056466:Histone Demethylases; C504076:KDM1a protein, mouse; D006655:Histone Deacetylases; D008239:Lysine
keywords: Glucocorticoid; Lysine deacetylase; Lysine demethylase; Repression; Transcription