This Article Full Text Full Text (PDF) All Versions of this Article: 101/12/e115    most recent CIRCRESAHA.107.164178v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lockman, K. Articles by Mack, C. P. Search for Related Content PubMed PubMed Citation Articles by Lockman, K. Articles by Mack, C. P. Related Collections Restenosis Developmental biology Gene regulation Physiological and pathological control of gene expression Smooth muscle proliferation and differentiation

(Circulation Research. 2007;101:e115.)
© 2007 American Heart Association, Inc.

UltraRapid Communication

The Histone Demethylase, Jmjd1a, Interacts With the Myocardin Factors to Regulate SMC Differentiation Marker Gene Expression

Kashelle Lockman, Joan M. Taylor, Christopher P. Mack

From the Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill.

Correspondence to Christopher Mack, PhD, Department of Pathology, University of North Carolina, Chapel Hill, NC 27599-7525. E-mail cmack{at}med.unc.edu

We and others have previously shown that the myocardin transcription factors play critical roles in the regulation of smooth muscle cell (SMC) differentiation marker gene expression. In a yeast 2-hybrid screen for proteins that interact with myocardin-related transcription factor-A (MRTF-A), we identified the histone 3 lysine 9 (H3K9)-specific demethylase, Jmjd1a. GST pull-down assays demonstrated that Jmjd1a bound all 3 myocardin family members, and further mapping studies showed that the jumonjiC domain of Jmjd1a was sufficient to mediate this interaction. Overexpression of Jmjd1a in multipotential 10T1/2 cells decreased global levels of di-methyl H3K9, stimulated the SM -actin and SM22 promoters, and synergistically enhanced MRTF-A– and myocardin-dependent transactivation. Using chromatin immunoprecipitation assays, we also demonstrated that TGF-β–mediated upregulation of SMC differentiation marker gene expression in 10T1/2 cells was associated with decreased H3K9 dimethylation at the CArG-containing regions of the SMC differentiation marker gene promoters. Importantly, knockdown of Jmjd1a in 10T1/2 cells and primary rat aortic SMCs by retroviral delivery of siRNA attenuated TGF-β–induced upregulation of endogenous SM myosin heavy chain expression. These effects were concomitant with increased H3K9 dimethylation at the SMC differentiation marker gene promoters and with inhibition of MRTF-A–dependent transactivation of the SMC-specific transcription. These results suggest, for the first time, that SMC differentiation marker gene expression is regulated by H3K9 methylation and that the effects of the myocardin factors on SMC-specific transcription may involve the recruitment of Jmjd1a to the SMC-specific promoters.

Key Words: SRF • myocardin factors • histone methylation • jumonjiC domain • smooth muscle

This article has been cited by other articles:

				W. Zhou, S. Negash, J. Liu, and J. U. Raj Modulation of pulmonary vascular smooth muscle cell phenotype in hypoxia: role of cGMP-dependent protein kinase and myocardin Am J Physiol Lung Cell Mol Physiol, May 1, 2009; 296(5): L780 - L789. [Abstract] [Full Text] [PDF]

				S. Beyer, M. M. Kristensen, K. S. Jensen, J. V. Johansen, and P. Staller The Histone Demethylases JMJD1A and JMJD2B Are Transcriptional Targets of Hypoxia-inducible Factor HIF J. Biol. Chem., December 26, 2008; 283(52): 36542 - 36552. [Abstract] [Full Text] [PDF]

				P. A.C. Cloos, J. Christensen, K. Agger, and K. Helin Erasing the methyl mark: histone demethylases at the center of cellular differentiation and disease Genes & Dev., May 1, 2008; 22(9): 1115 - 1140. [Abstract] [Full Text] [PDF]