Mechanisms of Transcriptional Regulation in Chromatin

Stowers Institute For Medical Research, Kansas City MO

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Abstract

DESCRIPTION (provided by applicant): Revision to R37-GM047867. This revision application is in response to Notice Number NOT-OD-09-058, Notice Title: NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications. In response to FOA PA-07-070 this is a competitive revision to R37 GM047867 "Mechanisms of Transcriptional Regulation in Chromatin". The specific aims of the original application are to study the composition and functions of the SAGA histone acetyltransferase and other chromatin modifying complexes in Saccharomyces cerevisiae. In this revision application we propose to extend the aims of the proposal by analyzing the composition, targeting and function of the SAGA complex, in Drosophila melanogaster where its role in the developmental control of gene expression can be examined. The revision application contains 2 specific aims focusing on proteomic and genomic approaches to rapidly generate extensive data sets regarding the tissue-specific composition of the SAGA complex and its role in the developmental control of gene expression. The revision application adds two specific aims: 1. Identification and functional analysis of the subunits of the Drosophila SAGA complex and interacting factors. In this aim we will identify the remaining subunits of the SAGA complex. We will also purify the complex from specific tissues in developing embryos to identify any tissue-specific subunits of the complex and to identify transcription factors that interact with the complex in each tissue. 2. Genome-wide localization of the SAGA complex in specific tissues and analysis of its role in tissue-specific gene expression. In this aim we will use chromatin immunoprecipitation to identify the sites where SAGA is bound to the genome in each tissue. Through the analysis of mutant embryos we will identify the tissue specific genes requiring SAGA for expression. The data sets generated under the aims of this revision will strongly facilitate studies of the role of SAGA in development and facilitate our understanding of its roles in human disease. PUBLIC HEALTH RELEVANCE: Revision to R37-GM047867. The SAGA histone acetyltransferase complex is a major regulator of gene transcription implicated in the development of several forms of cancer and neurodegenerative disease. To understand the role of SAGA in development we will study its tissue specific localization to target genes and its role in tissue-specific gene expression in fruit flies. Learning the functions of SAGA in development will assist understanding its functions in human disease.