Interview with Jeannie T. Lee, MD, PhD
Department of Molecular Biology, Massachusetts General Hospital
Howard Hughes Medical Institute (HHMI)
Harvard Medical School, Department of Genetics
Session Chair/Speaker at the 9th Annual Meeting of the Oligonucleotide Therapeutics Society
Biography & Current Research:
Professor Jeannie T. Lee is an Investigator of the Howard Hughes Medical Institute and Professor of Genetics (and Pathology) at Harvard Medical School and the Massachusetts General Hospital (MGH). She is also the Scientific Founder of RaNA Therapeutics.
Dr. Lee specializes in the study of epigenetic regulation by long noncoding RNAs (lncRNA). Using X-chromosome inactivation (XCI) as a model, her laboratory has made several contributions to our understanding of RNA-directed chromatin change, including the role of RNA in targeting Polycomb complexes and the mechanisms of repression by antisense RNA. She received her A.B. in Biochemistry and Molecular Biology from Harvard University, where she worked on antisense repression of transposition with Nancy Kleckner.
She obtained M.D.-Ph.D degrees from the University of Pennsylvania School of Medicine, where she studied epigenetic regulation of X-linked diseases with Robert L. Nussbaum. At the Whitehead Institute/MIT, her postdoctoral work with Rudolf Jaenisch delineated the X-inactivation center. She has served as Chief Resident of Clinical Pathology at MGH, and received both the Basil O’Connor Scholar Award (March of Dimes) and the Pew Scholars Award (Pew Foundation) as a young investigator.
Dr. Lee has been awarded a Distinguished Graduate Award of the University of Pennsylvania School of Medicine, and currently holds a MERIT Award from the NIH. She is also the recipient of the 2010 Molecular Biology Prize from the National Academy of Sciences, U.S.A, is a Fellow of the American Association for the Advancement of Science (AAAS), and serves on the Board of Directors for the Genetics Society of America.
Q: How did you get involved in the antisense field? What were your preconceptions about antisense technology before getting involved?
A: Through serendipity. It began back in my university days, when I carried out undergraduate thesis work with Professor Nancy Kleckner. I studied regulation of a bacterial transposon known as “Tn10”. Its transposase gene is controlled by — you guessed it — an antisense RNA! It was one of the first to be discovered in prokaryotes. This transcript blocks translation of the transposase RNA. I made mutations in the antisense and showed that a stem-loop structure is required for this effect.
Then I left the antisense field for 13 years and stumbled into it again when I started my lab at MGH. While studying X-inactivation, we discovered that Xist RNA is controlled by, yes, yet another antisense RNA (one of the first described in mammals)! This one controls the sense gene by many different mechanisms.
We named it Tsix, the reverse complement of X-i-s-t. Thus, I came full circle and my fate was sealed. I had no preconceived notions of the antisense field, as I seem to have been in the field from the beginning. Antisense regulation works.
Q: What excites you most about the potential of research in long noncoding RNAs to expand our understanding of biology? What excites you most about long noncoding RNAs as drug targets?
A: Long noncoding RNAs probably outnumber coding mRNAs by 10 fold. While the vast majority of lncRNAs has not been characterized, a growing number of characterized examples shows us that (a) lncRNAs can control gene expression, (b) they can do so in a locus-specific manner, and (c) they serve as recruiting platforms for chromatin-modifying complexes. These features make them excellent drug targets.
Q: How did you get involved in long noncoding RNA research?
A: My involvement was serendipitous at first (Tn10 transposition), but Xist RNA piqued my interest after hearing about it at a conference in 1990. I decided to study it as a postdoc in the Jaenisch Lab, and then went on to identify its antisense regulator,Tsix, as an independent investigator. The X-inactivation center is an exemplary noncoding locus, as nearly every critical element is a long noncoding RNA. My lab has spent the past 16 years studying how these transcripts work.
We have been particularly excited by the discovery that Xist RNA binds and recruits Polycomb repressive complex 2 (PRC2) to the X-chromosome. This prompted us to search for other lncRNAs that associate with PRC2 and led to identification of thousands of PRC2-interacting transcripts.
RaNA Therapeutics was founded on the idea that these lncRNAs could be excellent drug targets. Emerging data suggest that this is indeed the case! The potential to translate our basic science discoveries to the clinic has been enormously satisfying.
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