It has long been puzzling how a relatively small number of transcription factors (TFs) can precisely control expression of ~21,000 ORFs and probably 10-fold more non-coding RNAs in humans. Another major gap in the transcription field is a lack of a simple set of rules that explain the specificity of protein-DNA interactions. These gaps represent a major problem because, until they are filled, understanding of the transcription circuitry and its underlining principles will remain highly incomplete. The long-term goals are to characterize the human protein-DNA interaction (PDI) network and elucidate the underlining molecular mechanisms of transcriptional regulation using the combined force of protein microarray technologies and bioinformatics. The objectives of this particular application are to identify a comprehensive list of sequence-specific unconventional DNA-binding proteins (uDBPs) and to better define rules that specify TF-DNA interactions. The central hypothesis is that unbiased, high-throughput profiling of PDIs will reveal rules and organization of transcriptional regulatory networks and pathways. This hypothesis has been formulated on the basis of preliminary data produced in the applicants The propose research is relevant to public health because generation of a comprehensive list of participants in human transcriptional control and regulation and characterization of the rules that define DNA-binding specificity is ultimately expected to increase understanding of diseases that result from defects in transcription factor function. The proposed research is thus relevant to part of the NIH's mission as this advance in fundamental biological knowledge will help identify better therapeutics for a broad range of human diseases.Public Health Relevance
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