Abnormalities in cholesterol and fatty acid homeostasis have been implicated in a number of common diseases, such as atherosclerosis, Alzheimer's disease, and cancers. SREBPs are critical regulators of genes controlling cholesterol and fatty acid homeostasis, hence elucidation of the molecular mechanism of transcription regulation by SREBPs could assist efforts to identify novel chemical modifiers of cholesterol and fatty acid biosynthesis that may have clinical utility. We will dissect the role of the ARC/Mediator coactivator in SREBP gene regulation.
The Specific Aims are: I. To determine the functional role of ARC/Mediator and the ARC105 subunit in gene activation by the SREBP family of transcription factors. We will determine the functional involvement of the ARC/Mediator and ARC 105 in transcription control by the SREBP family of activators using our chromatin based in vitro transcription system and RNAi followed by DNA microarray analysis. These studies will clarify the role of the ARC/Mediator in SREBP gene activation programs, and increase our understanding of the ARC105 subunit as a critical activator-target. II. To determine whether KIX domains in distinct co-activators serve as functionally important interaction modules for SREBPs. We will examine how SREBPs interact molecularly and functionally with the putative ARC105 KIX domain in comparison with the CBP and p300 KIX domains. These studies will determine whether KIX domains in different types of co-activators may serve as docking modules for SREBPs and will provide insights into how certain activators can bind multiple co-activators. III. To identify the molecular and functional interplay of activators and co-activators at SREBP target genes. We will use a combination of RNAi and chromatin immunoprecipitation (ChIP) to determine the dynamic interplay of SREBPs and the ARC/Mediator and CBP/p300 co-activators on different SREBP target genes in vivo. The proposed investigations will further our understanding of the individual, cooperative, or competitive roles of activators and KIX domain-containing co-activators and their recruitment dynamics in SREBP-dependent gene activation in vivo.
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