Drug abuse and addiction add a significant challenging dimension to our comprehension of the progression and treatment of HIV/AIDS. A promising class of HIV treatments (Histone Deacetylase Inhibitors, HDI) and psychostimulant drugs of abuse share a common denominator: both cause changes in chromatin structure through the acetylation of histones. The objective of the proposed research is to identify and analyze the functional chromatin regulatory networks associated with HDI and psychostimulant treatment by means of combined measurements of nucleosome distribution, gene expression, histone modifications, chromatin accessibility and nuclear architecture. The central hypothesis is that HDI and psychostimulants will induce distinct but overlapping patterns of chromatin structural change with specific functions in regulatory networks. The rationale for the proposed research is that a catalogue of chromatin regulatory events will link HDI and psychostimulants with specific genomic targets. Guided by strong preliminary data, the hypothesis will be tested by accomplishing two specific aims : (1) Identify HDI- and psychostimulant-induced chromatin and gene regulatory changes, and (2) Define the role of HDI- and psychostimulant-induced chromatin structural changes in complex genetic and epigenetic regulatory networks. The innovative collective use of microarray technology and cytological assays combined with an integrative systems biology analysis will allow the development new models describing the relationship between chromatin structure and genome regulation. This work will contribute a comprehensive view of the chromatin structural changes that different HDIs and psychostimulants have from their initial targets to the final nuclear readout of transcription. Thi contribution is significant because it will reveal specific sites of chromatin regulation for ten different HDIs and for four psychostimulants, providing the first comprehensive insights into the general and locus-specific mechanisms of these compounds in the context of HIV/AIDS. This work will also provide a detailed, comprehensive description of the relationships among fundamental aspects of genome regulation: histone acetylation, nucleosome distribution, chromatin accessibility, three-dimensional nuclear architecture, and transcription. This contribution is significant because the characterization of the cascade of nuclear events that elicit the chromatin regulatory changes will mark an important first step in understanding the crosstalk among the fundamental processes of genome regulation. This work will represent a new direction that will yield immediate and widely applicable mechanistic information that will aid in the design of effective strategies for the prevention and treatment of HIV/AIDS in drug abusing populations and further our understanding of fundamental chromatin biology.
The proposed research is relevant to public health because identification and analysis of functional chromatin regulatory networks represents a new direction that will yield fundamental mechanistic information applicable in the design of effective strategies for the prevention and treatment of HIV/AIDS in drug abusing populations. The proposed research is relevant to the NIH mission to seek fundamental knowledge about the nature and behavior of living systems (regulatory genomic organization) and the application of that knowledge to enhance health, lengthen life, and reduce the burdens of illness and disability (HIV/AIDS and drug abuse).
