Mechanisms of gene regulation by long noncoding RNAs - ABSTRACT Only about 1% of the mammalian genome encodes for protein yet 80% is transcribed, suggesting that noncoding RNA has many roles in gene regulation. Our research program aims to delineate those roles and the mechanisms involved. Over the next five years, our focus will be the study of long noncoding RNAs (lncRNAs) that function to repress transcription. The most potent repressive lncRNA, Xist, silences transcription across one entire X chromosome during the essential process of X-inactivation. Yet the mechanisms by which Xist and other lncRNAs repress transcription are insufficiently understood. Indeed, at the level of RNA sequence, it is unclear what distinguishes repressive lncRNAs from those that lack repressive activity. This same lack of clarity extends to lncRNAs of all functional classes. Thus, it remains nearly impossible to predict the function of lncRNAs from analyses of their sequence content, stifling progress in the field. At the same time, lncRNAs play critical roles in health. Abnormal expression of genes that lncRNAs target for repression can drive genetic disorders such as Angelman and Rett Syndromes, as well as cancers and autoimmunity. Moreover, uncharacterized lncRNAs are found throughout mammalian genomes, including in regions linked to phenotypic variation and disease, hinting that lncRNAs with therapeutic relevance remain to be discovered. Additionally, we have discovered that many intron-containing RNAs closely resemble known repressive lncRNAs. Although introns are better known for their roles as substrates in the context of splicing, our data raise the intriguing possibility that intronic portions of the nascent transcriptome mediate lncRNA-like regulatory effects. Over the next five years, our research program will reveal fundamental insights into lncRNA biology and transcriptional control that are relevant across cell types and organisms. We expect to determine how RNA sequence and structure confer repressive function to lncRNAs; define new connections between nascent RNAs, RNA processing, and epigenetic regulation; delineate new mechanisms through which RNAs use RNA-binding proteins to control transcription; and identify how the regulatory functions of lncRNAs are modulated by underlying features of the genome. Along the way, we will develop experimental and computational approaches that will enable regulatory RNAs and their mechanisms to be identified across biological systems. Given the centrality of gene regulation in human health and disease, we expect our work to lead to the discovery of etiologies and therapeutic opportunities in many settings.
