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Molecular and Cellular Biology, February 2006, p. 1307-1317, Vol. 26, No. 4
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.4.1307-1317.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Selective Repression of Low-Density Lipoprotein Receptor Expression by SP600125: Coupling of Histone H3-Ser10 Phosphorylation and Sp1 Occupancy

Wei Huang, Sanjay Batra, Sasi Korrapati, V. Mishra, and Kamal D. Mehta*

Department of Molecular and Cellular Biochemistry, The Ohio State University College of Medicine and Public Health, The Dorothy M. Davis Heart and Lung Research Institute, 333 Hamilton Hall, 1645 Neil Avenue, Columbus, Ohio 43210

Received 25 October 2005/ Returned for modification 20 November 2005/ Accepted 21 November 2005

In this study, we show that exposure of human hepatocellular HepG2 cells to SP600125 rapidly and dramatically reduced global histone H3-Ser10 phosphorylation, without significantly affecting the global acetylation of neighboring lysines. The loss of phosphorylation is not due to changes in cell cycle distribution and/or apoptosis and is mediated independent of either p46/54JNK or MSK-1/2 inhibition. Moreover, SP600125 repressed the basal expression of the endogenous LDL receptor in a gene-specific manner, whereas the expression of squalene synthase, sterol response element-binding protein-1, and ß-actin was not altered by SP600125. Finally, chromatin immunoprecipitation and in vivo footprinting assays provided direct evidence that localized histone H3-Ser10 dephosphorylation at the low-density lipoprotein receptor promoter was associated with a significant decrease in the occupancy of the Sp1 binding site, with a slight reduction in the occupancy of RNA polymerase II. Together, our findings show that SP600125 is an efficient inhibitor of histone H3-Ser10 phosphorylation in vivo, and our results led us to hypothesize that this modification plays a novel role in regulating transcriptional control by modulating promoter accessibility to maintain basal expression in a gene-specific manner.

* Corresponding author. Mailing address: Department of Molecular and Cellular Biochemistry, The Ohio State University College of Medicine and Public Health, 1645 Neil Avenue, Columbus, OH 43210. Phone: (614) 688-8451. Fax: (614) 292-4118. E-mail: mehta.80{at}osu.edu.

Molecular and Cellular Biology, February 2006, p. 1307-1317, Vol. 26, No. 4
0022-538X/06/$08.00+0     doi:10.1128/MCB.26.4.1307-1317.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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