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Molecular and Cellular Biology, January 2008, p. 863-872, Vol. 28, No. 2
0270-7306/08/$08.00+0     doi:10.1128/MCB.00960-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Naturally Extended CT · AG Repeats Increase H-DNA Structures and Promoter Activity in the Smooth Muscle Myosin Light Chain Kinase Gene{triangledown}

Yoo-Jeong Han and Primal de Lanerolle*

Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612

Received 30 May 2007/ Returned for modification 12 July 2007/ Accepted 25 October 2007

Naturally occurring repeat sequences capable of adopting H-DNA structures are abundant in promoters of disease-related genes. In support of this, we found (CT)22 · (AG)22 repeats in the promoter of smooth muscle myosin light chain kinase (smMLCK), a key regulator of vascular smooth muscle function. We also found an insertion mutation that adds another six pairs of CT · AG repeats and increases smMLCK promoter activity in spontaneously hypertensive rats (SHR). Therefore, we used the smMLCK promoters from normotensive and hypertensive rats as a model system to determine how CT · AG repeats form H-DNA, an intramolecular triplex, and regulate promoter activity. High-resolution mapping with a chemical probe selective for H-DNA showed that the CT · AG repeats adopt H-DNA structures at a neutral pH. Importantly, the SHR promoter forms longer H-DNA structures than the promoter from normotensive rats. Reconstituting nucleosomes on the promoters, in vitro, showed no difference in nucleosome positioning between the two promoters. However, chromatin immunoprecipitation analyses revealed that histone acetylations are greater in the hypertensive promoter. Thus, our findings suggest that the extended CT · AG repeats in the SHR promoter increase H-DNA structures, histone modifications, and promoter activity of the smMLCK, perhaps contributing to vascular disorders in hypertension.

* Corresponding author. Mailing address: Department of Physiology and Biophysics, University of Illinois at Chicago, 835 S. Wolcott, Chicago, IL 60612. Phone: (312) 996-6430. Fax: (312) 996-1414. E-mail: primal{at}uic.edu

{triangledown} Published ahead of print on 8 November 2007.

Molecular and Cellular Biology, January 2008, p. 863-872, Vol. 28, No. 2
0270-7306/08/$08.00+0     doi:10.1128/MCB.00960-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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