Epigenetic regulation of human α 1d -adrenergic receptor gene expression: a role for DNA methylation in Sp1-dependent regulation Gregory A. Michelotti * ,1 ,2 , D. Marshall Brinkley * ,1 , Daniel P. Morris * , Michael P. Smith * , Raphael J. Louie * and Debra A. Schwinn * ,† Departments of * Pharmacology/Cancer Biology, Anesthesiology, † Medicine (Cardiology) and Surgery, Duke University Medical Center, Durham, North Carolina, USA 2 Correspondence: Departments of Pharmacology/Cancer Biology, Anesthesiology, Duke University Medical Center, Durham, NC 27710. E-mail: miche007@mc.duke.edu A growing body of evidence implicates α 1 -adrenergic receptors (α 1 ARs) as potent regulators of growth pathways. The three α 1 AR subtypes (α 1a AR, α 1b AR, α 1d AR) display highly restricted tissue expression that undergoes subtype switching with many pathological stimuli, the mechanistic basis of which remains unknown. To gain insight into transcriptional pathways governing cell-specific regulation of the human α 1d AR subtype, we cloned and characterized the α 1d AR promoter region in two human cellular models that display disparate levels of endogenous α 1d AR expression (SK-N-MC and DU145). Results reveal that α 1d AR basal expression is regulated by Sp1-dependent binding of two promoter-proximal GC boxes, the mutation of which attenuates α 1d AR promoter activity 10-fold. Mechanistically, chromatin immunoprecipitation data demonstrate that Sp1 binding correlates with expression of the endogenous gene in vivo , correlating highly with α 1d AR promoter methylation-dependent silencing of both episomally expressed reporter constructs and the endogenous gene. Further, analysis of methylation status of proximal GC boxes using sodium bisulfite sequencing reveals differential methylation of proximal GC boxes in the two cell lines examined. Together, the data support a mechanism of methylation-dependent disruption of Sp1 binding in a cell-specific manner resulting in repression of basal α 1d AR expression.—Michelotti, G. A., Brinkley, D. M., Morris, D. P., Smith, M. P., Louie, R. J., Schwinn, D. A. Epigenetic regulation of human α 1d -adrenergic receptor gene expression: a role for DNA methylation in Sp1-dependent regulation. Key Words: transcription • cell-specific • promoter
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Epigenetic regulation of human α1d-adrenergic receptor gene expression: a role for DNA methylation in Sp1-dependent regulation
Michelotti, Gregory A.; Brinkley, D. Marshall; Morris, Daniel P.; Smith, Michael P.; Louie, Raphael J.; Schwinn, Debra A.
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, Volume 21 (9): 1979
Fed of American Socs for Experimental Biology – Jul 1, 2007
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