Stem Cell Center, Yale: Transcriptional Regulation of Stem and Progenitor Cells
Noncoding RNA-protein complexes (ncRNPs) are ubiquitous in eukaryotic cells and inhabit specific cellular compartments. The most famous noncoding nuclear RNPs(snRNPS) participate in pre-mRNA splicing by recognizing important intronsignals and assembling to form an active splicing complex called aspliceosome. There are many other kinds, including those where the RNA is made by an infecting virus. Our recent contributions to understanding the roles of ncRNA-protein complexes in mammalian gene expression include: 1) The discovery that splicing-like snRNPs are made by a virus to degrade a host microRNA. 2) Finding that a viral noncoding RNA possesses an element that forms a triple helix with the polyA tail that serves to stabilize the RNA in the nucleus.
Extensive Research Description
RNA-Protein Complexes: Roles in Gene Expression
Noncoding RNAs are important for every step of gene expression. We concentrate on nuclear noncoding RNAs complexed with proteins, where the most famous small nuclear RNPs (snRNPs) participate in pre-mRNA splicing. Current efforts are aimed at understanding how splicing influences downstream events in gene expression via the exon junction complex (EJC), how guide RNAs modify the snRNA components of snRNPs, and how microRNA biogenesis is regulated during the nuclear maturation steps. Some primate herpesviruses [Epstein-Barr virus (EBV), Herpesvirus saimiri (HVS), and Kaposi sarcoma virus (KSHV)] produce noncoding RNAs that associate with host cell proteins to form snRNPs. Recent investigations have studied the protein binding and nuclear localization of the EBERs of EBV, have revealed that the HSURs of HVS serve to upregulate genes that are hallmarks of T-cell activation in latently infected T cells — in part by binding and accelerating decay of a particular host microRNA, and have characterized an RNA element in the PAN RNA of KSHV that counteracts a rapid nuclear RNA decay pathway and solved its high resolution structure, revealing its mechanism of action. Viral microRNA biogenesis and function are also being studied.
- Guo, Y.E., and Steitz, J.A. (2014). Virus meets host microRNA: the destroyer, the booster, the hijacker. Molec. Cell Biol. 34, 3780-3787.
- Brown, J.A., Bulkley, D., Wang, J., Valenstein, M.L., Yario, T.A., Steitz, T.A., and Steitz, J.A. (2014). Structural insights into the stabilization of MALAT1 noncoding RNA by formation of a bipartite triple helix. Nat. Struct. Mol. Biol 21, 633-640. PMCI
- Guo, Y.E., Riley, K.J., Iwasaki, A., Steitz, J.A. (2014) Alternative capture of noncoding RNAs or protein-coding genes by Herpesviruses to alter host T-cell function. Molec. Cell 54, 67-79. PMCID: PMC4039351
- Moss, W.N., and Steitz, J.A. (2013). Genome-wide analyses of Epstein-Barr virus reveal conserved RNA structures and a novel stable intronic sequence RNA. BMC Genomics 14, 543. PMCID: PMC3751371
- Alexandrov, A., Colognori, D., Shu, M-D., and Steitz, J.A. (2012). Human spliceosomal protein CWC22 plays a role in coupling splicing to exon junction complex deposition and nonsense-mediated decay. Proc. Natl. Acad. Sci., USA. 109, 21313-21318. PMCID: PM
- Brown, J.A., Valenstein, M.L., Yario, T.A., Tycowski, K.T., and Steitz, J.A. (2012). Formation of triple-helical structures by the 3'-end sequences of MALAT1 and MENß noncoding RNAs. Proc. Natl. Acad. Sci., USA 109, 19202-19207. PMCID: PMC3511071
- Riley, K.J., Yario, T., and Steitz, J.A. (2012). Association of Argonaute proteins and microRNAs can occur after cell lysis. RNA 18, 1581-1585. PMCID: PMC3425773
- Lee, N., Pimienta, G., and Steitz, J.A. (2012). AUF1/hnRNP D is a novel protein partner of the EBER1 non-coding RNA of Epstein-Barr virus. RNA 18, 2073-2082. PMCID: PMC3479396
- Borah, S., Nichols, L.A., Hassman, L.M., Kedes, D.H., and Steitz, J.A. (2012). Tracking expression and subcellular localization of RNA and protein species using high-throughput single cell imaging flow cytometry. RNA 18, 1573-1579. PMCID: PMC3404377
- Riley, K.J., Rabinowitz, G.S, Yario, T., Luna, J., Darnell, R., and Steitz, J.A. (2012). EBV and human microRNAs co-target oncogenic and apoptotic viral and human genes during latency. EMBO J. 31, 2207–2221. PMCID: PMC3343464
- Nag, A., and Steitz, J.A. (2012). Tri-snRNP-associated proteins interact with subunits of the TRAMP and nuclear exosome complexes, linking decay to ongoing pre-mRNA splicing. RNA Biology 9, 334-342. PMCID: PMC3384585
- Tycowski, K.T., Shu, M.-D., Borah, S., Shi, M., and Steitz, J.A. (2012). Conservation of a triple-helix-forming RNA stability element in noncoding and genomic RNAs of diverse viruses. Cell Reports 2, 26-32. PMCID: PMC3430378
- Cazalla, D., Xie, M., and Steitz, J.A. (2011). A primate Herpesvirus uses the Integrator complex to generate viral microRNAs. Molec. Cell. 43, 982-992. PMCID: PMC3176678
- Borah, S., Darricarrère, N., Darnell, A., Myoung, J., and Steitz, J.A. (2011). A viral nuclear noncoding RNA binds re-localized poly(A) binding protein and is required for late KSHV gene expression. PLoS Pathogens. Oct;7(10):e1002300. PMCID: PMC3192849
- Martinez, I., Cazalla, D., Almstead, L., Steitz, J.A., and DiMaio, D. (2011). miR-29 and miR-30 regulate B-Myb expression during cellular senescence. Proc. Natl. Acad. Sci., USA 108, 522-527. PMCID: PMC3021067
- Alexandrov, A., Colognori, D., and Steitz, J.A. (2011). Human eIF4AIII interacts with an eIF4G-like partner, NOM1, revealing an evolutionarily conserved function outside the exon junction complex. Genes Dev. 25, 1078-1090. PMCID: PMC3093123
- Cazalla, D., and Steitz, J.A. (2011). Down-regulation of a host microRNA by a viral noncoding RNA. Nuclear Organization & Function (Cold Spring Harbor Symposia on Quantitative Biology LXXV). pp. 321-324. Cold Spring Harbor Laboratory Press, Cold Spring Ha
- Mortensen, R.D., Serra, M., Steitz, J.A., and Vasudevan, S. (2011). Posttranscriptional activation of gene expression in Xenopus laevis oocytes by microRNA-protein complexes (microRNPs). Proc. Natl. Acad. Sci., USA 108, 8281-8286 PMCID: PMC3100953
- Mitton-Fry, R.M., DeGregorio, S.J., Wang, J., Steitz, T.A., and Steitz, J.A. (2010). Poly(A) tail recognition by a viral RNA element through assembly of a triple helix. Science 330, 1244-1247. PMCID: PMC3074936
- Riley, K.J-L., Rabinowitz, G.S., and Steitz, J.A. (2010). Comprehensive analysis of rhesus lymphocryptovirus microRNA expression. J. Virol. 84, 5148-5157. PMCID: PMC2863793
- Cazalla, D., Yario, T., and Steitz, J.A. (2010). Downregulation of a host microRNA by a Herpesvirus saimiri noncoding RNA. Science 328,1563-1566.
- Pawlicki, J.M., and Steitz, J.A. (2010). Nuclear networking fashions RNA polymerase II transcripts for function. Trends in Cell Biology 20, 52-61. PMCID: PMC2821161