The precisely-regulated pattern of recruitment of DNA binding transcription factors and associated coactivators and corepressors underlies the critical events that regulate neurodevelopment and disease. We propose to validate 3 distinct technologies that will permit genome-wide promoter location analysis for these regulatory factors-ChlP-on-chip, ChlP-DASL-chip, and ChlP-RDA-for applications to test specific hypotheses in neurodevelopment and disease. Genome-wide promoter assays will be designed, constructed and validated and we will test these technologies by determining the pattern of cofactor binding in the genome. New siRNA approaches to profiling will be applied to validate occupied promoters as functional targets. We will focus on a method that provides the optimal sensitivity and applicability to gene tiling, and will generate a genome-wide murine promoter array and will tile a series of genomic intervals that will permit investigation of specific genomic loci to uncover epigenetic strategies used in signaldependent changes in gene activation/repression programs development. These include study of the roles of CaMKII delta and SMRT in early programs of neurodevelopment. This approach will permit testing of several hypotheses and will be used to identify the promoter-specific usage of key corepressors and coactivators and location of epigenetic marks. We believe that with validation of these approaches, technologies developed here will be of widespread utility in neuroscience, particularly in studies of development and neurodegenerative disease.
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