Regulation, evolution, and function of promoter-associated non-coding RNAs

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PROJECT SUMMARY / ABSTRACT LEIGHTON CORE, Ph.D. – UNIVERSITY OF CONNECTICUT= Proper regulation of RNA transcription is essential for dynamic control of cellular responses to environmental and developmental cues. Dogmatic shifts in the fields of transcription regulation and RNA biology have led us to appreciate that noncoding RNAs (ncRNAs) can regulate transcription of protein-coding genes by diverse mechanisms such as recruitment of activators or repressors to gene promoters and enhancers or by affecting RNA processing. In addition to the role of the RNA, the act of transcription itself can positively or negatively influence promoter activity when transcription patterns overlap. These observations suggest that regulation of ncRNA biogenesis adds an intricate layer of control to overall gene expression levels. This proposal aims to 1) identify the mechanisms that regulate ncRNA production and destruction, 2) determine ncRNA effect on local protein-coding gene transcription and RNA processing, and 3) investigate the ability of ncRNAs to as capacitors for evolution of new genes. The major obstacles in understanding the full impact of ncRNAs on gene transcription is comprehensive identification of non-coding transcripts and methods to functionally classify them. The work proposed here will develop new experimental and computational methods for comprehensive identification of transcripts and a classification scheme that will predict function. We will experimentally test our functional predictions and use the results to inform further revision of our classification system. We will focus on ncRNAs that overlap with or emanate from protein-coding promoters to determine if they are regulated by independent signaling pathways and whether their level of production influences expression from the protein- coding gene. Finally, using an evolutionary model to identify nucleotide changes associated with altered ncRNA transcript production and processing, we will identify and test mechanisms that are involved in ncRNA regulation and how they may serve as a platform for gene birth during evolution. These studies will create functional transcript annotations that will be a primary resource for those studying gene expression in any context. In addition, our investigation of ncRNA regulation and evolution will serve as foundational work towards determining how these transcripts affect development, disease, and acquisition of new phenotypes.