Retinoid-dependent Recruitment of a Histone H1 Displacement Activity by Retinoic Acid Receptor

Abstract

Targeted recruitment of histone acetyltransferase (HAT) activities by sequence-specific transcription factors, including the retinoic acid receptors (RARs) and retinoid X receptors (RXRs), has been proposed to lead to destabilization of nucleosomal cores by acetylation of core histones. However, biochemical evidence indicates that destabilization and depletion of linker H1 histones must also occur at the promoter regions of actively transcribing genes. Mechanisms by which nuclear receptors and other transcription factors affect the removal of histone H1 from transcriptionally silent chromatin have not been previously described. In this report, we show that RARs interact in a ligand-dependent manner with HMG-I, which is known to displace histone H1 from chromatin. We further show that HMG-I and a novel related protein, HMG-R, also interact with other transcription factors. Using sense and antisense constructs of HMG-I/R in transient transfection assays with a retinoid responsive reporter, we also demonstrate that HMG-I/R is important for retinoid dependent transcriptional activity of RAR. These findings suggest a step wise mechanism by which RARs and other transcription factors can cause a targeted unfolding of compact chromatin as a first step in transcriptional activation, which would then be followed by recruitment of HAT activity and subsequent events.Retinoic acid receptors and retinoid X receptors (RAR and RXR ␣, ␤, and ␥) are sequence-specific, ligand-dependent transcription factors belonging to the superfamily of steroid/thyroid/vitamin D 3 nuclear receptors (1). RAR-RXR 1 heterodimers induce gene expression in a ligand dependent manner through RA responsive elements (RAREs) present in the promoter regions of responsive genes (2). Recently, CBP/p300, Sug1/Trip1, TIF1, SRC-1/N-CoA1, TIF2/GRIP1, and ACTR have been identified as co-factors, which interact with RARs and other nuclear receptors in a ligand-dependent manner (3, 4). Biochemical evidence supports models involving depletion of the nucleosomal core as well as H1 histones at the promoter regions of actively transcribing genes. CBP/p300, its associated protein p/CAF, SRC-1, and ACTR have intrinsic histone acetyltransferase (HAT) activity (5-7). It has been proposed that recruitment of HAT activity by sequence-specific transcription factors leads to acetylation of core histones and a destabilization of the nucleosomal core, thereby facilitating transcriptional activation (8 -10). However, an earlier obligatory step in transcriptional activation involves an unfolding of the compact, 30-nm chromatin fiber, which results only from a displacement of the potent transcriptional repressor, histone H1, from chromatin (11, 12). Mechanisms by which nuclear receptors and other transcription factors affect this obligatory removal of histone H1 from transcriptionally silent chromatin have not been described previously. In this report, we provide evidence that RARs interact in a ligand-dependent manner with HMG-I, which is known to displace histone H1 from chromati...

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