Mechanism and biology of widespread distal 3'UTR utilization in the CNS

Sloan-Kettering Inst Can Research, New York NY

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Abstract

DESCRIPTION (provided by applicant): Mechanism and biology of widespread distal 3'UTR utilization in the CNS The 3' untranslated regions (3'UTRs) of messenger RNAs (mRNAs) are the predominant location of cis-regulatory sequences that mediate post-transcriptional gene regulation. 3'UTRs can impart profound positive or negative regulatory impact on gene function, via diverse RNA binding proteins (RBPs) and short RNAs termed microRNAs (miRNAs). In recent years, it has been appreciated that alternative polyadenylation (APA) can induce 3'UTR variation according to cell-state, tissue identity or environmental condition, providing a strategy for coordinate post-transcriptional regulation of hundreds of genes. However, the molecular mechanisms of APA are mostly unknown and only for a few genes have the consequences of disrupting APA been studied in intact animals. We recently described broad tissue-specific APA trends in Drosophila, including substantial 3'UTR lengthening in the central nervous system. This included hundreds of unannotated extensions, ranging into lengths unprecedented for experimentally- validated 3'UTRs of stable transcripts detected by Northern analysis. Our ongoing unpublished efforts reveal that these principles are broadly conserved in the mammalian brain. Altogether, the existence of these unexpectedly broad and long 3'UTR extensions has strong implications for gene regulation in the nervous system. In particular, we hypothesize that they mediate critical aspects of the unique post-transcriptional needs of neurons, imposed by their unusual cellular architecture. Our extensive preliminary data are the basis of diverse experimental strategies that we propose to elucidate the genomic breadth, the biological utility, and mechanistic underpinning to neural 3'UTR lengthening in Drosophila and mammalian systems. The proposed work exploits our established expertise with transcriptome analysis, miRNAs, post-transcriptional control, and neural development and function. We believe that the knowledge gained from our mechanistic and functional studies will have direct relevance for human disease. Dysfunction of the neuronal APA network may induce neurological conditions, while ectopic activation of the 3'UTR lengthening mechanism should severely distort gene regulatory networks outside of the brain. Our multi-faceted research program should illuminate these processes.