Epigenetic regulation by RAR? maintains ligand-independent transcriptional activity.

ABSTRACT: Retinoic acid receptors (RARs) ?, ? and ? are key regulators of embryonic development. Hematopoietic differentiation is regulated by RAR?, and several types of leukemia show aberrant RAR? activity. Through microarray expression analysis, we identified transcripts differentially expressed between F9 wild-type (Wt) and RAR? 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 RAR? 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 RAR? knockout cells. We demonstrated specific association of RAR? and RXR? with the Mest promoter. Importantly, stable expression of a dominant negative, oncogenic PML-RAR? fusion protein in F9 Wt cells recapitulated the decreased Mest transcript levels observed in RAR? knockout cells. We propose that RAR? plays an important role in cellular memory and imprinting by regulating the CpG methylation status of specific promoter regions.

SUBMITTER: Laursen KB 

PROVIDER: S-EPMC3245912 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature