Department of Pharmacology
Ph.D., Molecular Biology
- epigenetic control by long noncoding RNAs, genomics, stem cells, cancer, human genetic disorders
Long non-coding RNAs (lncRNAs) are a newly appreciated class of regulatory molecule with fundamental roles in human health. The human genome encodes approximately 10,000 lncRNA genes, which are loosely defined as transcribed genomic regions, greater than 200 bases in length, that have little to no protein-coding potential. While the majority of lncRNAs have not been studied in any context, initial works suggest they represent a potent collection of RNA-based cofactors that control a range of cellular processes, most notably the regulation of gene expression. Defects in lncRNA-mediated gene regulation underlie several diseases, including types of cancer, where they affect metastasis, cell division, angiogenesis, and the control of cell death. Our long-term mission is to define in detail the mechanisms by which lncRNAs regulate gene expression, and use this knowledge to develop novel therapeutics, with a focus on cancer.
Our current efforts aim to understand the mechanisms by which certain lncRNAs control the large-scale epigenetic silencing of protein-coding gene clusters in mammals. Flagship examples of this type of regulation occur in the case of X-chromosome inactivation (XCI), where the Xist lncRNA is required for silencing of the entire set of genes along one X-chromosome, and in the case of autosomal imprinting, where certain lncRNAs induce the silencing of megabase-sized clusters of genes in a parent-of-origin specific fashion. The mechanisms by which lncRNAs target genes for repression in these scenarios remain unclear.
We take a genomics-centered, multidisciplinary approach to interrogate XCI, autosomal imprinting, and other lncRNA-mediated phenomena in mouse and human. We are particularly interested in defining lncRNA function in stem cells, given their developmental capacity, therapeutic potential, and utility as disease models.
Motivated graduate students and post-doctoral fellows interested in joining the group are encouraged to contact Dr. Calabrese via email.
Click above for PubMed publications.
Mugford J.W., Starmer J., Williams R.L. Jr, Calabrese J.M., Mieczkowski P., Yee D., Magnuson T. (2014) Evidence for Local Regulatory Control of Escape from Imprinted X Chromosome Inactivation. Genetics. 197(2):715-723. PMC4005674 Abstract
Williams R.L. Jr, Starmer J., Mugford J.W., Calabrese J.M., Mieczkowski P., Yee D., Magnuson T. (2014) fourSig: a method for determining chromosomal interactions in 4C-Seq data. Nucleic Acids Res. 42(8): e68. Abstract
- King I.F., Yandava C.N., Mabb A.M., Hsiao J.S., Huang H.S., Pearson B.L., Calabrese J.M., Starmer J., Parker J.S., Magnuson T., Chamberlain S.J., Philpot B.D., Zylka M.J.(2013) Topoisomerases facilitate transcription of long genes linked to autism. Nature 501(7465): 58-62. PMC3767287 Abstract
- Calabrese, J.M. and Magnuson, T. (2013) Roles of long noncoding RNAs in X-chromosome inactivation. In The Molecular Biology of Long Non-coding RNAs. Coller, J. and Khalil, A. (Eds.), Springer Science. 69-94.
- Calabrese, J.M., Sun, W. Song, L., Mugford, J.W., Williams, L., Yee, D., Starmer, J., Mieczkowski, P., Crawford, G.E., Magnuson, T. (2012) Site-specific silencing of regulatory elements as a mechanism of X-inactivation. Cell 151(5): 951-63. PMC3511858 Abstract | Press Release
- Fedoriw, A.M., Calabrese, J.M., Mu, W., Yee, D., Magnuson, T. (2012) Differentiation-Driven Nucleolar Association of the Mouse Imprinted Kcnq1 locus. Genes, Genomes, Genetics 2(12): 1521-8. PMC3516474 Abstract
- Zheng, G.X.*, Ravi, A.*, Calabrese, J.M., Medeiros, L.A., Kirak, O., Dennis, L.M., Jaenisch, R., Burge, C.B., Sharp P.A.. (2011) A latent pro-survival function for the mir-290-295 cluster in mouse embryonic stem cells. PLoS Genet. 7(5): e1002054. PMC3088722 Abstract
- Seila, A.C.*, Calabrese, J.M.*, Levine, S.S., Yeo, G.W. Rahl, P.B, Young, R.A., and Sharp, P.A.( 2008) Divergent transcription from active promoters. Science 322:1849-1851. PMC2692996 Abstract
- Calabrese, J.M.*, Seila, A.C.*, Yeo, G.W., and Sharp, P.A. (2007) RNA sequence analysis defines Dicer's role in mouse embryonic stem cells. Proc Natl Acad Sci USA 104(46): 18097-18102. PMC2084302 Abstract