Abstract
Chromatin modification is considered to be a fundamental mechanism of regulating gene expression to generate coordinated responses to environmental changes, however, whether it could be directly regulated by signals mediated by G protein-coupled receptors (GPCRs), the largest surface receptor family, is not known. Here, we show that stimulation of delta-opioid receptor, a member of the GPCR family, induces nuclear translocation of beta-arrestin 1 (betaarr1), which was previously known as a cytosolic regulator and scaffold of GPCR signaling. In response to receptor activation, betaarr1 translocates to the nucleus and is selectively enriched at specific promoters such as that of p27 and c-fos, where it facilitates the recruitment of histone acetyltransferase p300, resulting in enhanced local histone H4 acetylation and transcription of these genes. Our results reveal a novel function of betaarr1 as a cytoplasm-nucleus messenger in GPCR signaling and elucidate an epigenetic mechanism for direct GPCR signaling from cell membrane to the nucleus through signal-dependent histone modification.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylation
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Active Transport, Cell Nucleus / physiology
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Animals
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Arrestins / genetics
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Arrestins / metabolism*
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Cell Line
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Cell Nucleus / metabolism*
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Chromatin / metabolism
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Cyclin-Dependent Kinase Inhibitor p27 / genetics
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Cyclin-Dependent Kinase Inhibitor p27 / metabolism
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Epigenesis, Genetic
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Gene Expression Regulation*
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Histones / metabolism*
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Humans
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Mice
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Mice, Knockout
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Promoter Regions, Genetic
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Proto-Oncogene Proteins c-fos / genetics
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Proto-Oncogene Proteins c-fos / metabolism
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Receptors, G-Protein-Coupled / genetics
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Receptors, G-Protein-Coupled / metabolism*
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Receptors, Opioid, delta / genetics
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Receptors, Opioid, delta / metabolism*
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Signal Transduction / physiology
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Transcription, Genetic*
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beta-Arrestin 1
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beta-Arrestins
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p300-CBP Transcription Factors / metabolism
Substances
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ARRB1 protein, human
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Arrb1 protein, mouse
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Arrestins
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Chromatin
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Histones
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Proto-Oncogene Proteins c-fos
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Receptors, G-Protein-Coupled
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Receptors, Opioid, delta
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Recombinant Fusion Proteins
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beta-Arrestin 1
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beta-Arrestins
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Cyclin-Dependent Kinase Inhibitor p27
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p300-CBP Transcription Factors