Epigenetic regulation by RARα maintains ligand-independent transcriptional activity.

TitleEpigenetic regulation by RARα maintains ligand-independent transcriptional activity.
Publication TypeJournal Article
Year of Publication2012
AuthorsLaursen KB, Wong P-M, Gudas LJ
JournalNucleic Acids Res
Volume40
Issue1
Pagination102-15
Date Published2012 Jan
ISSN1362-4962
KeywordsAmino Acid Transport System A, Calcium-Binding Proteins, Embryonal Carcinoma Stem Cells, Gene Expression Profiling, Gene Knockout Techniques, Genomic Imprinting, Intracellular Signaling Peptides and Proteins, Ligands, Oncogene Proteins, Fusion, Promoter Regions, Genetic, Proteins, Receptors, Retinoic Acid, Retinoic Acid Receptor alpha, Retinoid X Receptor alpha, RNA, Messenger, Transcription, Genetic
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.

DOI10.1093/nar/gkr637
Alternate JournalNucleic Acids Res.
PubMed ID21911359
PubMed Central IDPMC3245912
Grant ListR01 CA043796 / CA / NCI NIH HHS / United States
R01CA043796 / CA / NCI NIH HHS / United States