Prof. Phillip A Sharp

MicroRNAs (miRNAs) are encoded by endogenous genes and regulate over half of all genes in mammalian cells. They regulate gene expression at the stages of translation and mRNA stability. Developing methods to physically identify the target mRNAs for particular miRNAs is on going. The surprising recent finding that expression of certain microRNAs can induce a pluripotent stem cell indicates that this mechanism of cytoplasmic regulation rivals that of transcription factors in the nucleus. RNA interference (RNAi) has dramatically expanded the possibilities for genotype/phenotype analyses in cell biology. Investigations into the mechanisms responsible for the activities of short interfering RNAs (siRNAs) are underway with the objective of increasing their effectiveness in gene silencing. Delivery of siRNAs by nanoparticles to silence genes in tumors is being tested in ovarian tumor models. High throughput sequencing of RNA populations revealed the generation of small RNAs in divergent transcription in mammalian cells. The role of this pervasive transcription from the anti-sense strand is under investigation. It is likely that these anti-sense transcripts are unstable because, in contrast to the sense transcript, they are not recognized by the certain RNA splicing factors. The same high throughput technology allows definition of alternatively spliced isoforms. Shifts in isoforms are common in cancer versus normal cells. Also, recent results from other labs have suggested that chromatin structure is related to control of alternative splicing. We are investigating these processes and, in particular, the relationship between elongation of transcription, RNA splicing and chromatin modifications.