"My vision is that by deciphering the fundamental principles of how IncRNAs work in normal cells, we can understand why their disruption leads to various human cancers and utilize this knowledge to develop specific therapeutics in cancer treatment."
- Dr. Mitchell Guttman
- Assistant Professor in the Division of Biology and Biological Engineering, California Institute of Technology
About DSA-Funded Research
Cellular regulation involves the coordinated activity of multiple proteins, yet how these proteins are organized and how they change across different cellular conditions is largely unknown. Our previous results suggest that large non-coding RNAs (IncRNAs) act as scaffolds to assemble protein complexes to control cell-type specific gene expression programs. As many IncRNAs interact with diverse chromatic regulators, a hypothesis is that IncRNAs work by localizing regulatory proteins to specific genomic DNA locations. We recently showed that the Xist IncRNA spreads across the X-chromosome by searching in 3-dimensions and modifies chromatin structure to spread to new genes. While this provided important insights into IncRNA localization, it it still unclear how IncRNAs achieve specificity to target locations. Answering this question will require a different approach, one where we can map the localization of all IncRNAs at high resolution. Here, we will develop an innovative method to map the localization of all IncRNAs to genomic DNA. Using this approach, we will map the localization of all IncRNAs across a time course of cellular reprogramming. We will determine the sequences required for recruitment to specific sites and we will determine their roles in repositioning gene targets during this process. Because many IncRNAs are known to act as tumor suppressor genes and oncogenes, understanding the localization principles of IncRNAs will provide a framework for understanding how mutations in IncRNAs lead to aberrant gene expression and give rise to human cancer.
"When Mitch was a graduate student, I posed him a tricky problem on his first day in my lab. It was the last time that I needed to pose a question to him: he ran with this question and is still running! He has proven himself to be an extraordinary scientist in both experimental and computational work, having made a major discovery and pursued it brilliantly and relentlessly."
Eric S. Lander, Ph.D.
Broad Institute of MIT and Harvard
"Although Mitch was still a graduate student when we offered him a job at Caltech, the breadth and depth of his research in both computational and experimental areas were spectacular even when compared to scientists at much later career stages."
Stephen L. Mayo, Ph.D.
California Institute of Technology