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Targeted histone H4 acetylation via phosphoinositide 3-kinase- and p70s6-kinase-dependent pathways inhibits iNOS induction in mesangial cells

Departments of ¹Internal Medicine and of ²Integrative Biology, Pharmacology, and Physiology, The University of Texas Medical School at Houston, and the ³Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, Houston, Texas

Submitted 5 August 2005 ; accepted in final form 14 September 2005

The inducible nitric oxide synthase (iNOS) gene plays an important role in the response to and propagation of injury in glomerular mesangial cells. Although several cis and trans regulatory factors have been characterized, epigenetic regulation of the iNOS gene has not been considered extensively. In this report, we explored the role of histone acetylation in interleukin (IL)-1-mediated iNOS induction in cultured murine mesangial cells. Treatment of cells with the histone deacetylase inhibitor trichostatin A (TSA, 200 nM) resulted in a time-dependent, selective increase in histone H4 acetylation. TSA treatment of cells stably transfected with an iNOS promoter-luciferase construct inhibited IL-1 induction of endogenous nitric oxide and iNOS protein production and iNOS promoter-luciferase activity. Chromatin immunoprecipitation assays revealed that, under basal conditions, acetylated histone H4 associated with the region –978 to –710 of the iNOS promoter, a region rich in gene control elements and that IL-1 significantly increased this binding, which was further accentuated by cotreatment with TSA. Blockade of the phosphoinositide 3-kinase pathway with LY-294002 or the p70s6-kinase pathway with rapamycin in the presence of TSA and IL-1 inhibited ³⁸⁹Thr phosphorylation of p70s6 kinase, promoted binding of acetylated histone H4 to the iNOS promoter, and further suppressed iNOS protein expression and iNOS promoter activity. Thus TSA diminishes IL-1-induced iNOS transcription through phosphoinositide 3-kinase- and p70s6 kinase-dependent pathways that increase site-specific histone H4 acetylation at the –978 to –710 region of the iNOS promoter. This novel epigenetic control mechanism extends the network of regulatory controls governing NO production in mesangial cells.

epigenetic; nitric oxide; transcription

This article has been cited by other articles:

				Z. Yu, T. Kuncewicz, W. P. Dubinsky, and B. C. Kone Nitric Oxide-dependent Negative Feedback of PARP-1 trans-Activation of the Inducible Nitric-oxide Synthase Gene J. Biol. Chem., April 7, 2006; 281(14): 9101 - 9109. [Abstract] [Full Text] [PDF]