title: Epigenetic regulation by RARα maintains ligand-independent transcriptional activity.
abstract: Retinoic acid receptors (RARs) α, β and γ are key regulators of embryonic development. Hematopoietic differentiation is regulated by RARα, and several types of leukemia show aberrant RARα activity. Through microarray expression analysis, we identified transcripts differentially expressed between F9 wild-type (Wt) and RARα knockout cells cultured in the absence or presence of the RAR-specific ligand all trans retinoic acid (RA). We validated the decreased Mest, Tex13, Gab1, Bcl11a, Tcfap2a and HMGcs1 transcript levels, and increased Slc38a4, Stmn2, RpL39l, Ref2L, Mobp and Rlf1 transcript levels in the RARa knockout cells. The decreased Mest and Tex13 transcript levels were associated with increased promoter CpG-island methylation and increased repressive histone modifications (H3K9me3) in RARα knockout cells. Increased Slc38a4 and Stmn2 transcript levels were associated with decreased promoter CpG-island methylation and increased permissive histone modifications (H3K9/K14ac, H3K4me3) in RARα knockout cells. We demonstrated specific association of RARα and RXRα with the Mest promoter. Importantly, stable expression of a dominant negative, oncogenic PML-RARα fusion protein in F9 Wt cells recapitulated the decreased Mest transcript levels observed in RARα knockout cells. We propose that RARα plays an important role in cellular memory and imprinting by regulating the CpG methylation status of specific promoter regions.
authors.affiliation: Pharmacology Department of Weill Cornell Medical College of Cornell University, NY 10065, USA.
authors.forename: Kristian B
authors.initials: KB
authors.lastname: Laursen
authors.forename: Pui-Mun
authors.initials: PM
authors.lastname: Wong
authors.forename: Lorraine J
authors.initials: LJ
authors.lastname: Gudas
mesh_terms: D026924:Amino Acid Transport System A / Q000235:genetics; D002135:Calcium-Binding Proteins; D054278:Embryonal Carcinoma Stem Cells; D020869:Gene Expression Profiling; D055786:Gene Knockout Techniques; D018392:Genomic Imprinting; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008024:Ligands; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D000072482:Retinoic Acid Receptor alpha; D047490:Retinoid X Receptor alpha / Q000378:metabolism; D050777:Stathmin; D014158:Transcription, Genetic
chemical_list: D026924:Amino Acid Transport System A; D002135:Calcium-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D015514:Oncogene Proteins, Fusion; D011506:Proteins; D012333:RNA, Messenger; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D047490:Retinoid X Receptor alpha; C420522:Slc38a4 protein, mouse; D050777:Stathmin; C512849:Stmn2 protein, mouse; C103637:mesoderm specific transcript protein; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein