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* Center of Molecular Immunology and Infectious Diseases, Department of Veterinary and Biomedical Sciences,
Center for Gene Regulation, Department of Biochemistry and Molecular Biology,
Graduate Program in Pathobiology, Pennsylvania State University, University Park, PA 16802; and
Department of Medicine, Center for HIV/AIDS Care and Research, Boston University School of Medicine, Boston, MA 02118-2393
Efficient HIV-1 transcription requires the induction of cellular transcription factors, such as NF-
B, and the viral factor Tat, which through the recruitment of P-TEFb enhances processive transcription. However, whether cellular signals repress HIV-1 transcription to establish proviral latency has not been well studied. Previously, it has been shown that the receptor tyrosine kinase RON inhibits HIV transcription. To gain insights into the biochemical mechanisms by which RON inhibits transcription we examined the binding of transcription factors to the HIV provirus long terminal repeat using chromatin immunoprecipitation. RON expression decreased basal levels of NF-B and RNA polymerase II (Pol II) binding to the HIV provirus long terminal repeat but did not prevent the induction of these complexes following treatment with cytokines. However, RON did decrease efficient transcription elongation because reduced RNA Pol II was associated with HIV-1 genomic sequences downstream of the transcriptional start site. There was a correlation between RON expression and increased binding of factors that negatively regulate transcription elongation, NELF, Spt5, and Pcf11. Furthermore, the ability of RON to inhibit HIV-1 transcription was sensitive to a histone deacetylase inhibitor and was associated with nucleosome remodeling. These results indicate that RON represses HIV transcription at multiple transcriptional check points including initiation, elongation and chromatin organization and are the first studies to show that cellular signaling pathways target Pol II pausing to repress gene expression.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Penn State Tobacco Formula Funds (to A.J.H.) and by Grants R01 HL066571 (to P.A.H.), GM47477 (to D.S.G.), and AI62467 (to A.J.H.) from the National Institutes of Health.
2 A.K. and Z.Z. contributed equally to this work.
3 Current address: Division of Basic Sciences, Immunobiology Working Group, Fox Chase Cancer Center, Philadelphia, PA 19111-2497.
4 Address correspondence and reprint requests to Dr. Andrew J. Henderson, Department of Medicine, Section of Infectious Diseases, Center for HIV/AIDS Care and Research, Evans Biomedical Research Center, Boston University School of Medicine, 650 Albany Street, Boston, MA 02118-2393. E-mail address: andrew.henderson{at}bmc.org
5 Abbreviations used in this paper: LTR, long terminal repeat; TAR, Tat-activating region; ChIP, chromatin immunoprecipitation; NELF, negative elongation factor; Pol II, polymerase II; LM-PCR, ligation-mediated PCR; DSIF, DRB sensitivity-inducing factor; TSA, trichostatin A.
This article has been cited by other articles:
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  P. Kalantari, O. F. Harandi, P. A. Hankey, and A. J. Henderson HIV-1 Tat Mediates Degradation of RON Receptor Tyrosine Kinase, a Regulator of Inflammation J. Immunol., July 15, 2008; 181(2): 1548 - 1555. [Abstract] [Full Text] [PDF]
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