Dr. Michael C. Yu
Office: 355 Cooke Hall
Office Hours: for 402/502 course: Weds & Thurs, 9AM-12PM or by appointment
Tel: (716) 645-4931
Ph.D. University of California, Los Angeles
Postdoctoral Research at Harvard Medical School
A majority of cellular proteins undergo post-translational modifications. The purpose of these modifications is to serve as cellular molecular switches and to increase proteomic repertoire of a cell. Recently, protein arginine methylation has emerged as a major regulator of protein function. This modification is catalyzed by a family of evolutionarily conserved enzyme called protein arginine methyltransferase (PRMT. In the metazoans, protein arginine methylation has been shown to play a role in the differentiation and development as well as etiology of human diseases such as multiple sclerosis, spinal muscular atrophy, and cancer. Using both yeast and mammalian cells as model organisms, my lab is focused on understanding the biological functions of protein arginine methylation at the molecular level using cell biological, biochemistry, proteomics, and genomics approaches.
The Role of Protein Arginine Methylation in pre-mRNA Splicing
During gene expression, pre-mRNAs are processed by a multitude of RNA processing factors, including components of the spliceosomal complex, and packaged into messenger ribonucleoparticles (mRNPs) before being exported to the cytoplasm as mature, translatable mRNAs. Since mRNP biogenesis involves an intricate web of cross-stimulatory connections and physical interdependencies, the formation of an export-competent mRNP requires that such processing factors be recruited onto nascent transcripts co-transcriptionally, and in a very precise order. In yeast, ordered association of the spliceosomal components during transcription facilitates efficient co-transcriptional mRNA processing, but the mechanisms regulating these ordered associations remain largely unknown. Previous studies from our laboratory, using yeast Saccharomyces cerevisiae, demonstrated that the major protein arginine methyltransferase (PRMT) Hmt1 plays an important role in proper co-transcriptional recruitment of a number of mRNA processing factors. We identified Snp1, a U1 snRNP component, as a substrate of Hmt1. Cells lacking Hmt1 or its catalytic activity display changes in the co-transcriptional recruitment to the genomic targets for a number of splicing factors. Our lab is currently trying to understand the molecular mechanism by which Hmt1 modulates the recruitment as well as other aspects of pre-mRNA splicing.
Modulation of RNA Pol III Transcription by Protein Arginine Methylation
Recently, we have discovered a new role for yeast Hmt1 in the control of RNA polymerase III (RNAPIII)-mediated transcription. Specifically, we uncovered a genome-wide enrichment of yeast PRMT1 (termed Hmt1) at tRNA genes. Moreover, we found that Hmt1 loss-of-function mutants display elevated levels of tRNAs, and that Hmt1 physically associates with Bdp1, a component of the RNAPIII transcription factor complex TFIIIB, and Rpc82, an RNAPIII subunit. Currently, we are investigating the molecular mechanism by which Hmt1 modulates tRNA biogenesis. Given the high degree of conservation between human PRMT1 and yeast Hmt1, as well as that of the process of RNAPIII transcription throughout eukaryotes, we expect the insights provided from our work to be applicable to human cells.
- Likhite, N., Jackson, C.A., Liang, M-S., Krzyzanowski, M.C., Lei, P., Wood, J.F., Birkaya, B., Michaels, K.L., Andreadis, S.T., Clark, S.D., Yu, M.C. and Ferkey, D.M. (2015) The protein arginine methyltransferase PRMT5 regulates D2-like dopamine receptor signaling. Science Signaling. 8(402):ra115.
- Jackson, C.A. and Yu, M.C. (2014) Detection of Protein Arginine Methylation in Saccharomyces cerevisiae. Methods Mol. Biol. 1163:229-47.
- Krzyzanowski, M.C., Ezak, M.J., Brueggemann, C., Wood, J.F., Michaels, K.L., Jackson, C.A., Collins, K.D., Yu, M.C., L’Etoile, N.D., and Ferkey, D.M. (2013) The C. elegans cGMP-dependent Protein Kinase EGL-4 Regulates Nociceptive Behavioral Sensitivity. PLoS Genetics. Jul;9(7):e1003619
- Milliman, E.J., Hu, Z., and Yu, M.C. (2012) Genomic Insights of Protein Arginine Methyltransferase Hmt1 Binding Reveals Novel Regulatory Functions. BMC Genomics.13(1):728
- Jackson, C.J., Yadav, N., Min, S., Li, J., Milliman, E.J., Qu, J., Chen, Y-C., and Yu, M.C. (2012) Proteomic Analysis of Interactors for Yeast Protein Arginine Methyltransferase Hmt1 Reveals Novel Substrate and Insights into Additional Biological Roles. Proteomics. Sep 20. doi:10.1002/pmic.201200132
- Milliman, E.J., Yadav, N., Chen, Y-C., Muddukrishna, B., Karunanithi, S., and Yu, M.C. (2012) Recruitment of Rpd3 to the Telomere Depends on the Protein Arginine Methyltransferase Hmt1. PLoS ONE. 7(8):e44656.
- Yu, M.C. (2011) The Role of Protein Arginine Methylation in mRNP Dynamics. Mol. Biol. Int. 2011:16382
- Chen, Y-C., Milliman, E.J., Goullet, I., Cote, J., Vollbracht, J.A., and Yu, M.C. (2010) Protein Arginine Methylation Facilitates Co-transcriptional Recruitment of Pre-mRNA Splicing Factors. Mol. Cell. Biol. 30(21):5245-56.
- Hoke, S.M., Mutiu, I.A., Genereaux, J., Kvas, S., Buck, M., Yu, M.C., Gloor, G.B., and Brandl, C.J. (2010) Mutational Analysis of the C-terminal FATC Domain of Saccharomyces cerevisiae Tra1. Curr. Genet. 56(5):447-65
- Moore, M.J., Schwartzfarb, E.M., Silver, P.A., and Yu, M.C. (2006) Differential Recruitment of the Splicing Machinery During Transcription Predicts Genome-wide Patterns of mRNA Splicing. Mol. Cell. 24(6):903-15. *Article was highlighted by a Faculty of 1000 “Must Read” rating
- Yu, M.C., Lamming, D.W., Eskin, J.A., Sinclair, D.A., and Silver, P.A. (2006) The Role of Protein Arginine Methylation in the Formation of Silent Chromatin. Genes Dev. 20(23):3249-3254
- Tsankov, A., Brown, C.R., Yu, M.C., Win, M., Silver, P.A., and Casolari, J.M. (2006) Communication between levels of transcriptional control improves robustness and adaptivity. Mol Syst Biol. 2:65
- Yu, M.C., Bachand, F., McBride, A.E., Komili, S., Casolari, J.M., and Silver, P.A. (2004) Arginine methyltransferase affects interaction and recruitment of mRNA processing and export factors. Genes Dev. 18(16):2024-35
- Article was highlighted by News & Views in Nat. Struct. Mol. Biol (2004) Oct; 11(10):914-5.
- Article was highlighted by a Faculty of 1000 “Recommended” rating.
- Hieronymus, H., Yu, M.C., and Silver, P.A. (2004) mRNA Surveillance is Coupled to mRNA export. Genes Dev. 18(21):2652-62.