Tracking Large Non-Coding RNAs that Act on Chromatin
The importance of RNAs in biological regulation extends far beyond directing protein synthesis. Non-protein-coding RNAs (ncRNAs) function in diverse biological pathways and can play important roles in the development of disease. For example, the ~18kb large ncRNA (lncRNA) Xist drives repression of an entire mammalian chromosome. The loss of Xist can cause cancer in mice. The vast scope of lncRNA function is becoming clear thanks to progress in genome-wide analyses and sequencing technologies. These advances have revealed thousands of developmentally regulated lncRNAs with expression patterns that are specific to the cell type, and a handful have validated functions. On one hand, lncRNAs pose substantial challenges because many biochemical approaches developed to study proteins are ill-suited to study lncRNAs; on the other hand, lncRNAs provide an exciting opportunity to uncover new principles of biological regulation.
The work in the Simon lab focuses on understanding the molecular basis for epigenetic memory through the study of chromatin with a focus on chromatin-acting lncRNAs. While chromatin is central to the maintenance of cellular identity, our understanding of chromatin has been focused primarily on proteins and DNA. Yet lncRNAs (such as Xist) are also known to play important roles in epigenetics and transcriptional regulation through their influence on chromatin. Where do these lncRNAs act on chromatin? What are the direct biochemical roles of these RNAs? How do their activities integrate into what we already know about the regulation of chromatin? How are lncRNAs themselves dynamically regulated? To address these questions, we are developing new chemical and biochemical technologies with the long-term goal of integrating lncRNAs into our understanding of the dynamic regulation of chromatin.