Abstract
Heterotrimeric G-protein signal transduction initiated by G-protein-coupled receptors (GPCRs) in the plasma membrane is thought to propagate through protein-protein interactions of subunits, Gα and Gβγ in the cytosol. In this study, we show novel nuclear functions of Gβγ through demonstrating interaction of Gβ(2) with integral components of chromatin and effects of Gβ(2) depletion on global gene expression. Agonist activation of several GPCRs including the angiotensin II type 1 receptor specifically augmented Gβ(2) levels in the nucleus and Gβ(2) interacted with specific nucleosome core histones and transcriptional modulators. Depletion of Gβ(2) repressed the basal and angiotensin II-dependent transcriptional activities of myocyte enhancer factor 2. Gβ(2) interacted with a sequence motif that was present in several transcription factors, whose genome-wide binding accounted for the Gβ(2)-dependent regulation of approximately 2% genes. These findings suggest a wide-ranging mechanism by which direct interaction of Gβγ with specific chromatin bound transcription factors regulates functional gene networks in response to GPCR activation in cells.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Amino Acid Motifs / genetics
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Amino Acid Sequence
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Angiotensin II / pharmacology
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Animals
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Cell Nucleus / genetics
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Cell Nucleus / metabolism
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Cells, Cultured
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Chromatin / genetics
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Chromatin / metabolism*
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GTP-Binding Protein beta Subunits / genetics
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GTP-Binding Protein beta Subunits / metabolism*
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GTP-Binding Protein gamma Subunits / genetics
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GTP-Binding Protein gamma Subunits / metabolism*
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Gene Expression Profiling
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Gene Expression Regulation / drug effects
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Gene Regulatory Networks
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HEK293 Cells
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Histones / genetics
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Histones / metabolism
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Humans
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Immunoblotting
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MEF2 Transcription Factors
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Mice
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Mice, Inbred C57BL
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Molecular Sequence Data
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Myogenic Regulatory Factors / genetics
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Myogenic Regulatory Factors / metabolism
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Protein Binding
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RNA Interference
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Receptor, Angiotensin, Type 1 / genetics
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Receptor, Angiotensin, Type 1 / metabolism
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Receptors, G-Protein-Coupled / genetics
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Receptors, G-Protein-Coupled / metabolism*
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Sequence Homology, Amino Acid
Substances
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Chromatin
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GTP-Binding Protein beta Subunits
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GTP-Binding Protein gamma Subunits
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Histones
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MEF2 Transcription Factors
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Myogenic Regulatory Factors
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Receptor, Angiotensin, Type 1
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Receptors, G-Protein-Coupled
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Angiotensin II