Chromatin-based mechanisms of dynamic gene expression/repression

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Our laboratory focuses on chromatin-based mechanisms of gene regulation by the conserved Notch signaling pathway. Upon ligand binding, the nuclear factor RBP-J activates transcription of target genes whereas in the absence of signaling, RBP-J switches off target gene expression by assembling a corepressor complex. Recently, we have biochemically and functionally characterized several key components of the corepressor complex. Here, we propose to further characterize the coactivator complex and a histonemethyltransferase complex that keeps target genes ‘responsive’ (AIM 1). We will define the chromatin context at Notch target genes throughout the genome and gain insights into the molecular mechanisms at selected promoters (AIM 2). Finally, combining the data provided by the genome-wide analysis together with an unbiased functional genomic approach (RNAi screen), we will assess impact of novel chromatin modifiers on target genes (AIM 3). The successful execution of this project would significantly advance our understanding of chromatin-based mechanisms of gene regulation by signal transduction pathways and may help to discover novel therapeutic targets for Notch-associated diseases.