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The Journal of Neuroscience, March 30, 2005, 25(13):3350-3357; doi:10.1523/JNEUROSCI.0186-05.2005
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Cellular/Molecular
Retinoic Acid-Induced Chromatin Remodeling of MouseOpioid Receptor Gene
Sung Wook Park, * M. D. Mostaqul Huq, * Horace H. Loh, andLi-Na Wei Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota 55455
The mouse
opioid receptor (KOR) gene is constitutively expressed in P19 embryonic stem cells but is first suppressed and reactivated during retinoic acid (RA)-induced neuronal differentiation. However, no RA response element (RARE) can be found in this gene regulatory region. The suppression and reactivation of the KOR gene in this neuronal differentiation model suggested chromatin remodeling occurred on this gene promoter triggered by RA induction. This study asks whether RA induces alteration in the nucleosomal structure of this gene promoter that has no apparent RARE and, if so, how RA remodels chromatin of this promoter. The results revealed two loose nucleosomes, N1 at -44 (3' boundary) from the transcription initiation site and N2 spanning the transcription initiation site, that are relevant to active transcription. RA formed a repressive chromatin configuration of this promoter by compacting nucleosome N1, followed by nucleosome N2 condensation. Chromatin immunoprecipitation assay demonstrated RA induced replacement of the c-Myc/Max complex with the Max/Mad1 complex on the E box located within nucleosome N1, coinciding with reduced Sp1 binding to GC boxes located within nucleosome N2 and recruitment of chromatin remodeling factor Brahma-related gene 1 (BRG-1) to this promoter. Consistently, histone deacetylation, Lys9 methylation, and hypophosphorylation of RNA polymerase II C-terminal domain were detected on this promoter after RA treatment. It is concluded that RA induces KOR gene suppression, as early neuronal differentiation marker, by inducing substitution of c-Myc/Max with Max/Mad on the E box and by BRG-1 involved nucleosome recruitment and chromatin condensation, thereby abolishing Sp1 binding.
Key words: retinoic acid;
Received Sep 10, 2004; revised February 15, 2005; accepted February 16, 2005.
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