Abstract
Gene induction by retinoic acid (RA) is suppressed by overexpression of receptor-interacting protein 140 (RIP140). RIP140-mediated suppression was reversed most effectively by overexpressing the coactivator p300/CREB-binding protein-associated factor (P/CAF). Immunoprecipitation demonstrated coexistence of holoreceptors complexed with RIP140 or P/CAF. Chromatin immunoprecipitation revealed rapid RA-enhanced recruitment of RIP140, but delayed P/CAF recruitment, to an RA-targeted promoter in COS-1 cells supplemented with RIP140. In RA-induced P19 cells, endogenous RIP140 was rapidly (within 4 h) and significantly recruited to both the RARbeta2 and TR2 genes, whereas the peak of endogenous P/CAF recruitment occurred much later (48 h) and to a lesser degree. Consistent with these observations, significant histone acetylation of endogenous RA receptor (RAR) targets was only observed 48 h following RA treatment. In vitro experiments confirmed RA-induced transcription from a chromatin template, which was reduced by adding RIP140. This study presents evidence for coexistence of multiple RAR-coregulator complexes and a preferential RA-induced recruitment of RIP140 to endogenous RAR-targeted promoters after short term RA treatment, which correlates with suppressed induction of RA-regulated gene expression in the presence of RIP140.
Highlights
Eukaryotic gene regulation is achieved by a complex network of events that results in alteration of chromatin structures and coregulator recruitment to the transcription machinery [1, 2]
This study presents evidence for coexistence of multiple RA receptor (RAR)-coregulator complexes and a preferential retinoic acid (RA)-induced recruitment of receptor-interacting protein 140 (RIP140) to endogenous RAR-targeted promoters after short term RA treatment, which correlates with suppressed induction of RA-regulated gene expression in the presence of RIP140
The activation of reporter gene activity by introduction of RAR1⁄7RXR and RA could be further enhanced by overexpression of TIF2, p300, and protein-associated factor (P/CAF) (Fig. 1A, columns 3, 5, and 6 versus column 2)
Summary
Eukaryotic gene regulation is achieved by a complex network of events that results in alteration of chromatin structures and coregulator recruitment to the transcription machinery [1, 2]. Our recent studies on retinoic acid (RA)-inducible systems suggested a model for the novel action of RIP140 in hormonal regulation of gene expression [22,23,24] This involves two features of RIP140: its interaction with nuclear hormone receptors in a hormone-dependent manner and its ability to recruit histone deacetylase to the nuclear receptors and to their target DNAs in the presence of hormones. Several issues are addressed, including altered levels of RA-induced receptor-mediated gene activation as a result of changing levels of coregulators, the dynamics of RIP140 and p300/CREB-binding proteinassociated factor (P/CAF) recruitment to an RA reporter gene and two endogenous RA-regulated gene promoters, and the direct effect of RIP140 on the in vitro transcription efficiency of RA-responsive genes assembled into chromatin templates
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