Long Intervening Noncoding RNAs (lincRNAs): Develo.. (FLAME)
Long Intervening Noncoding RNAs (lincRNAs): Developmental Functions and Molecular Mechanisms of Action
Start date: Feb 1, 2014,
End date: Jan 31, 2019
Genome-wide studies have revealed that the majority of vertebrate genomes are transcribed and generate large numbers of long intervening noncoding RNAs (lincRNAs). While there is growing evidence that these molecules have functional importance for diverse cellular processes, such as dosage compensation, transcriptional regulation, and reprogramming, the role of lincRNAs in normal development remains elusive. To better understand the function and evolution of lincRNAs, we previously identified over 550 lincRNAs expressed during zebrafish embryonic development. We demonstrated that at least two of these novel lincRNAs, megamind and cyrano, are required for proper embryonic development, in particular for brain morphogenesis and neurogenesis. Remarkably, lincRNA functionality is retained in mammalian orthologs despite rapid evolution and little sequence conservation between human and zebrafish lincRNAs (Ulitsky*, Shkumatava* et al., Cell, 2011).This proposal aims to identify conserved developmental functions of novel lincRNAs and to determine the molecular mechanisms that drive these lincRNA functions (Aims 1 and 2). For mechanistic studies, the initial focus will be on cyrano and megamind. Preliminary evidence suggests that one of these novel molecular mechanisms is through a non-canonical interaction between cyrano and the miRNA pathway (Aim 3). Furthermore, we will investigate the relationship between conserved genomic positions of lincRNAs across vertebrate genomes and their conserved biological functions (Aim 4). The specific aims outlined in this proposal will identify novel regulatory RNAs with important and potentially conserved roles in vertebrate embryonic development, and provide mechanistic insights into how specific lincRNA contribute to normal development. Moreover, we anticipate that this project will contribute to a new synthesis of knowledge of genome function and regulation.
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