Institute Professor and Professor of Biology
KI Research Area of Focus:
Institute Professor and Professor of Biology
KI Research Area of Focus:
"The Sharp Laboratory focuses on the biology and technology of small RNAs and other types of non-coding RNAs. RNA interference (RNAi) has dramatically expanded the possibilities for genotype/phenotype analysis in cell biology and for therapeutic intervention. MicroRNAs (miRNAs) are encoded by endogenous genes and regulate primarily at the stages of translation and mRNA degradation over half of all genes in mammalian cells. The Sharp Laboratory is working to identify physically the target mRNAs for particular miRNAs. Most promoters and enhancers in mammalian cells are transcribed divergently with RNA polymerases initiating in both directions. Divergent transcription generates thousands of short non-coding RNAs. These divergent nascent RNAs are thought to facilitate the formation of a condensate promoting a burst of transcription. How this process is regulated by DNA binding transcription factors is being investigated currently. The extent of elongation by polymerase in either the sense direction or the antisense direction is controlled by recognition of the nascent RNA by U1 snRNP, a spliceosome component. The functions of condensates are also being investigated in relationship to RNA splicing, chromatin modifications and transcription."
Phillip A. Sharp is Institute Professor (highest academic rank) at the Massachusetts Institute of Technology, member of the Department of Biology and the Koch Institute for Integrative Cancer Research. He joined the Center for Cancer Research (now the Koch Institute) in 1974 and served as its director for six years, from 1985 to 1991, before taking over as head of the Department of Biology, a position he held for the next eight years. More recently, he was founding director of the McGovern Institute, a position he held from 2000 to 2004. His research interests have centered on the molecular biology of gene expression relevant to cancer and the mechanisms of RNA splicing. His landmark work in 1977 provided the first indications of “discontinuous genes” in mammalian cells. The discovery fundamentally changed scientists' understanding of gene structure and earned Dr. Sharp the 1993 Nobel Prize in Physiology or Medicine. Dr. Sharp has authored over 400 papers. He is an elected member of the National Academy of Sciences, the Institute of Medicine, the American Academy of Arts and Sciences, the American Philosophical Society, and the Royal Society, UK. Among his many awards are the Gairdner Foundation International Award, the Lasker Basic Medical Research Award, and the National Medal of Science. His long list of service includes the presidency of the AAAS (2013) and Chair of the Scientific Advisory Committee, SU2C Project, AACR.
Dr. Sharp is a member of the board of directors of the Whitehead and Broad Institutes, and chairs the advisory boards of the MIT Museum and the Jameel Clinic at MIT. Dr. Sharp is a co-founder of Biogen and Alnylam Pharmaceuticals Inc. He is a member of the advisory board of Polaris Venture Partners; chairman of the scientific advisory board and member of the board of directors, Alnylam Pharmaceuticals; advisor and investor, Longwood and Polaris Venture Funds; member of the boards of directors at Syros Pharmaceuticals and Vir Biotechnology; and member of the scientific advisory board, Dewpoint Therapeutics and Skyhawk Therapeutics. A native of Kentucky, Dr. Sharp earned a BA degree from Union College, Barbourville, KY, and a PhD in chemistry from the University of Illinois, Urbana-Champaign in 1969.
For further details about the Sharp Lab, click here.
We have recently reported that divergent transcription is common of promoter sites for genes in embryonic stem cells (see Figure). These promoters have an RNA polymerase initiated in the sense direction immediately downstream of the transcription start site and a second polymerase initiated in the antisense direction, about 250 base pairs upstream. Surprisingly, the antisense polymerase is controlled by elongation processes very similar to those of sense polymerase. For example, both require P-TEFb activity for elongation beyond about 50 nts. The nature of factors or sequences that differentiate the effective elongation of the polymerase in the sense direction as compared to the ineffective elongation in the anti-sense direction remains to be fully identified but appears to involve recognition of nascent RNA by U1 snRNP.
Long non-coding RNAs (lncRNAs) have been described from analysis of deep RNA sequencing from many types of mammalian cells. Comparable RNA species have also been reported from sequencing data of yeast and Drosophila. Recent analysis of several large data sets of RNA sequences expressed in embryonic stem cells shows that a majority of long non-coding RNAs originated from initiation sites that are divergent from known protein-encoding genes or sites with chromatin marks indicating enhancer elements. Both short RNAs and lncRNAs probably function in regulation of genes in cis by promoting the formation of a large condensate containing RNA polymerase, mediator complex and other factors to generate a burst of transcription at a nearby promoter site.
Gene sequences important for accurate splicing of the nuclear precursors to mRNAs are commonly conserved during evolution. We are using computational methods to identify, by comparison of genomic sequences from multiple organisms, intron and exon sequences which are important for accurate splicing and for control of alternative RNA splicing. RNA binding proteins, snRNPs, and regulatory factors control formation of condensates encompassing introns and exons to execute intron removal through formation of a spliceosome. We are investigating the relationship between condensate formation and chromatin structure, transcription and RNA binding factors in control of alternative RNA splicing.
Guo YE, Manteiga JC, Henninger JE, Sabari BR, Dall'Agnese A, Hannett NM, Spille JH, Afeyan LK, Zamudio AV, Shrinivas K, Abraham BJ, Boija A, Decker TM, Rimel JK, Fant CB, Lee TI, Cisse II, Sharp PA, Taatjes DJ, Young RA. (2019). Pol II phosphorylation regulates a switch between transcriptional and splicing condensates. Nature, 572(7770), 543–548. https://doi.org/10.1038/s41586-019-1464-0
Hnisz D, Shrinivas K, Young RA, Chakraborty AK, Sharp PA. A Phase Separation Model for Transcriptional Control. Cell, 169(1), 13-23 (2017).
Ravi AR, Gurtan AM, Kumar MS, Chin C, Jacks T, Sharp PA. Proliferation and tumorigenesis of a murine sarcoma cell line in the absence of DICER1. Cancer Cell 21, 848-55 (2012).
Leung AKL, Vyas S, Rood JE, Bhutkar A, Sharp PA, Chang P. Poly(ADP-ribose) regulates stress responses and microRNA activity in the cytoplasm. Mol. Cell 42, 489-99 (2011).
Ventura A, Young AG, Winslow MM, Lintault L, Meissner A, Erkeland SJ, Newman J, Bronson RT, Crowley D, Stone JR, Jaenisch R, Sharp PA, Jacks, T. Targeted deletion reveals essential and overlapping functions of the miR-17~92 family of miRNA clusters. Cell 132, 875-886 (2008). PMCID: PMC2323338
Seila AC, Calabrese JM, Levine SS, Yeo GW, Rahl B, Young RA, Sharp PA. Divergent transcription from active promoters. Science 322, 1849-1851 (2008). NIHMSID: 94606
Sandberg R, Neilson JR, Sarma A, Sharp PA, Burge, C. Widespread evasion of posttranscriptional regulation associated with proliferation. Science, 320, 1643-1647 (2008). PMCID: PMC2587246