Gene expression regulation by RNA methylation

Dr. Chuan He is the John T. Wilson Distinguished Service Professor in the Department of Chemistry and Department of Biochemistry and Molecular Biology at the University of Chicago. He received his bachelor of science degree in 1994 from the University of Science and Technology of China and his Ph.D. in chemistry from the Massachusetts Institute of Technology in 2000, studying under professor Stephen J. Lippard. After training as a Damon-Runyon postdoctoral fellow with professor Gregory L. Verdine at Harvard University, he joined the University of Chicago as an assistant professor, rising to associate professor in 2008 and full professor in 2010. He was selected as an investigator of the Howard Hughes Medical Institute in 2013. Dr. He’s research spans a broad range of fields including chemical biology, RNA biology, epigenetics, biochemistry, and genomics. His recent research concerns reversible RNA and DNA methylation in biological regulation. In 2011, his group discovered reversible RNA methylation as a new mechanism of gene expression regulation. His laboratory characterized the RNA m⁶A methyltransferase complex and several key reader proteins that bind preferentially to m⁶A-modified RNA and regulate their stability and translation. This new layer of post-transcriptional regulation broadly affects cancer initiation and progression as well as signaling in the tumor microenvironment. In 2020, Dr. He’s laboratory reported prevalent m⁶A methylation on chromatin-associated regulatory RNAs (carRNAs), which regulates chromatin state and global transcription. The reversible methylation of carRNA controls mammalian and plant development. More recently, his group discovered chromatin regulation by carRNA m⁵C methylation, a pathway that critically impacts tumorigenesis. His laboratory also spearheaded the development of enabling technologies to study RNA and DNA modifications as well as gene expression regulation.

About the Lecture

Over 170 types of post-transcriptional RNA modifications have been identified in all kingdoms of life. We have discovered RNA demethylation and shown that reversible RNA modification could impact a wide range of biological processes. We have also characterized proteins that selectively recognize m⁶A-modified mRNA and affect the translation status and lifetime of the target RNA. I will present our discoveries on chromatin state regulation by chromatin-associated regulatory RNA (carRNA) methylation. We found that carRNAs contain different chemical marks which facilitate recruitment of chromatin factors to shape local and global chromatin state. We also found that transgenic expression of mammalian FTO enhances crop yield by demethylating carRNA and altering chromatin states, while plant m⁶A demethylases, homologous to mammalian ALKBH5, primarily act on mRNA and show minimal effects on growth. We uncover intrinsically disordered regions (IDRs) as regulatory restraint regions (RRRs) that limit chromatin engagement of RNA demethylases. Modulation of these IDRs allowed us to engineer plant demethylases that enhance Arabidopsis root growth and boost rice yield. These findings explain the divergent substrate specificities of FTO and ALKBH5 and establish a scalable, plant-compatible approach for chromatin reprogramming and crop improvement.