Long noncoding RNAs (lncRNAs) have emerged as pervasive features of the mammalian genome with recent annotations identifying >50,000 lncRNAs in humans. Despite their prevalence, few of these transcripts have been functionally characterized. While multiple lines of evidence point to roles for lncRNAs in chromatin and transcription regulation, rigorous definition of the physiological effects of these molecules remains rare. However, our recent work has identified an evolutionarily conserved physiological role for a lncRNA that binds p53, further demonstrating that lncRNAs contribute to critically important cellular processes. The realization that lncRNAs can bind p53 and modulate p53 function establishes a new paradigm for information input onto p53, one in which alterations in the transcriptional landscape of cells may inform global reprograming of p53 physiological responses. In this proposal, we will systematically examine the role of p53-bound lncRNAs in cellular stress responses. We will leverage recent technical advances in genome-wide transcription engineering by CRISPR to systematically modulate the expression of p53-bound lncRNA expression and examine the the physiological consequences. The long term goals of our lab are to: (i) identify the repertoire of long noncoding RNAs that participate p53-dependent physiological processes and (ii) characterize the molecular mechanisms of these molecules with the goal of (iii) understanding how lncRNAs affect human health and disease in order to modulate them for therapeutic gain. The research program outlined here represents the first steps aimed at achieving these goals.
In this grant application, we propose to study the molecular mechanisms and functional roles of a class of cellular macromolecule called long noncoding RNA. The goal of this proposal is to understand how long noncoding RNAs affect the function of the p53 tumor suppressor protein, a central control hub that coordinates many different types of defenses against cellular stresses. We will use a multifaceted approach to identify long noncoding RNAs that bind to p53, characterize how they affect p53's functions, and determine how long noncoding guide p53 to mobilize the correct set of defenses to respond to a given cellular stress.
