Gene-specific transcriptional silencing directed by dephosphorylation of RNAP II

University Of Texas At Austin, Austin TX

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Abstract

DESCRIPTION (provided by applicant): The transcription process in eukaryotic cells is controlled by the C-terminal domain of RNA polymerase II through its post-translational modification states. However enzymes that recognize the same phosphorylation site in CTD can lead to different transcriptional outcomes. To address the central question that how gene-specific regulation was achieved by CTD regulatory enzymes; we investigate the structure function mechanism of Scp, a human CTD Ser5 phosphatase that functions as a co-repressor for neuronal gene expression. By comparing gene-specific CTD phosphatase Scp, to general-transcription CTD phosphatase Ssu72, we will test two different yet not mutually exclusive hypotheses to explain the differentiated transcription outcomes: molecular targeting and gene-specific CTD code. Finally, we will identify neuronal genes that are subject to Scp regulation and develop chemical tools to investigate the gene expression cascade during neurogenesis. The research breaks new ground in understanding CTD-directed transcription regulation. The chemical compounds developed in this study will become powerful tools to understand the biological mechanism of neuronal stem cell differentiation. Finally, the study of Scp-directed gene silencing in various cell types pave the way to establish if Scp can be a valid drug target for neurodegenerative diseases such as Alzheimer's.