ROLE OF CHROMATIN IN HIV TRANSCRIPTIONAL REGULATION

J. David Gladstone Institutes, San Francisco CA

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Abstract

Description (Adapted from Applicant's abstract): This application seeks to study the role of chromatin in the transcriptional regulation of the HIV-1 LTR. The applicant has previously mapped the sites of nucleosomes on the LTR and found that a single nucleosome, nuc1, is specifically disrupted upon activation of the promoter. In addition, inhibitors of histone disacetylases cause HIV activation. This application proposes to define the putative repressive role of nuc1 by introducing mutations that disrupt its binding and will examine if the nucleosome is displaced or is modified upon activation. The histone deacetylase and DNA -binding factors that mediate repression of the LTR will be identified, and the role of Tat in disrupting the nucleosome will be evaluated. Finally, the applicant will use an in vitro transcription system reconstituted with purified histones to evaluate the effects of specific mutations in the histone amino tails (sites of acetylation) on HIV expression.