Yongsheng Shi

Associate Professor, Microbiology & Molecular Genetics
School of Medicine

Ph.D., Syracuse University, 2002, Biology

B.S., Nankai University, China, 1996, Molecular Biology

Phone: (949) 824-0358
Fax: (949) 824-8598
Email: yongshes@uci.edu

University of California, Irvine
B235, Med Sci I
Mail Code: 4025
Irvine, CA 92697

picture of Yongsheng  Shi

Stem cell, mRNA processing, cancer, omics
URL Shi lab website
2012: American Cancer Society Research Scholar Award
Post-transcriptional Gene Regulation in Stem Cells and Cancer Development

We are broadly interested in post-transcriptional gene regulation and its role in stem cell biology and in cancer development. Our current focus is on the mRNA 3' end processing. The 3' ends of most eukaryotic mRNAs are formed by an endonucleolytic cleavage and the subsequent addition of a string of adenosines. Interestingly, the transcripts of ~70% of genes in all eukaryotes have alternative 3' ends that are formed by cleavage/polyadenylation at different sites, a phenomenon called mRNA alternative polyadenylation (APA). APA not only expands the proteomic and functional diversity, but also plays important roles in gene regulation. Deregulation of mRNA 3' processing and APA have been implicated in a wide spectrum of human diseases. However, it remains poorly understood how poly(A) sites are recognized and how their recognition is regulated. Our goal is to decipher the rules that govern poly(A) site choice, or the “polyadenylation code”, by using a combination of biochemical, genomic, and genetic approaches. Our studies aim to provide novel insights into the basic mechanisms of post-transcriptional gene regulation as well as its role in many physiological and pathological processes..

1. mRNA APA regulation in stem cells and cancer.
We have recently developed a high throughput sequencing-based method called PAS-seq for quantitatively RNA polyadenylation profiling at the transcriptome level. Using this method, we detected extensive changes in the global APA profile during stem cell differentiation to neurons that, in most cases, lead to 3' UTR lengthening (Shepard et al., RNA 2011). Recently we have identified the protein Fip1 as a critical regulator of the global APA profile and we have demonstrated that Fip1-mediated APA regulation is essential for embryonic stem cell self-renewal and for somatic reprogramming (Lackford et al., EMBO J 2014). These studies revealed an unexpected role for post-transcriptional gene regulation in stem cell biology. Given the similarities between stem cells and cancer cells, we are also investigating whether and how APA regulation may contribute to cancer development.

2. Characterization of the mRNA 3' processing machinery.
Previously we have purified the human mRNA 3' processing complex in its active and intact form (Shi et al., Mol Cell 2009). Surprisingly, this complex consists of more than 85 proteins, including the core 3' processing factors and many peripheral factors that may couple mRNA 3' end formation to other cellular processes. Currently we are carrying out proteomic, structural and functional analyses to understand the inner workings of this amazing molecular machine. Recently we have mapped the RNA interactions for some of the core mRNA 3' processing factors (Yao et al., PNAS 2012; Yao et al., RNA 2013) and our results revealed a surprising diversity in the mechanisms for poly(A) site recognition in mammalian cells.
Publications 1. Shi, Y., Reddy, B. & Manley, JL. (2006) PP1/PP2A phosphatases are required for the second step of pre-mRNA splicing and target specific snRNP proteins. Mol Cell. 23(6): 819-29.

2. Shi, Y. & Manley, JL. (2007) A complex signaling pathway in response to heat shock regulates SRp38 phosphorylation and pre-mRNA splicing. Mol Cell. 28(1): 79-90.

3. Shi, Y., Giammartino, DD., Sharkeshik, A., Taylor, D., Rice, W, Yates, JR, 3rd, Frank, J. & Manley, JL. (2009) Molecular architecture of the human pre-mRNA 3’ processing complex. Mol Cell. 33(3): 365-76.

4. Shi, Y., Chan, S., & Martinez-Santibañez, G. (2009) An up-close look at the pre-mRNA 3’ processing complex. RNA Biol. 6(5):522-5.

5. Shepard, PJ., Choi, E., Lu, J., Flanagan, LA., Hertel, KJ., & Shi, Y. (2011) Complex and dynamic landscape of RNA polyadenylation revealed by PAS-Seq. RNA. 17(4) 761-772.

6. Chan, S., Choi, E., & Shi, Y. (2011) Pre-mRNA 3’-end processing complex assembly and function. Wiley Interdisciplinary Reviews: RNA. 2: 321-35

7. Shi, Y. (2012) Alternative polyadenylation: new insights from global analyses. RNA 18: 2105-2117. (Invited review)

8. Yao, C., Biesinger, J., Wan, J., Weng, L., Busch, A., Xing, Y., Xie, X., & Shi, Y. (2012) Transcriptome-wide analyses of CstF64-RNA interactions in global regulation of mRNA alternative polyadenylation. Proc Natl Acad Sci U S A. 109 (46): 18773-8.

9. Giammartino, DD., Shi, Y., & Manley, JL. (2013) PARP1 Represses PAP and Inhibits Polyadenylation during Heat Shock. Molecular Cell 49: 1-11.

10. Yao, C., Choi, E., Weng, L., Xie, X., Wan, J., Xing, Y., Moresco, JJ., Tu, PG., Yates, JR, 3rd. & Shi, Y. (2013) Overlapping and distinct functions of CstF64 and CstF64t in mammalian mRNA 3' processing. RNA 19: 1-10.

11. Wang, L., Miao, Y., Zheng, X., Lackford, B., Zhou, B., Han, L., Yao, C., Ward, J., Burkholder, A., Fargo, DC., Shi, Y., Williams, CJ., & Hu, G. The THO complex regulates pluripotency gene mRNA export to control embryonic stem cell self-renewal and somatic cell reprogramming. Cell Stem Cell 13: 676-690.

12. Lackford, B., Yao, C., Charles, GM., Weng, L., Zheng, X., Choi, EA., Xie, X., Wan, J., Xing, Y., Freudenberg, JM., Yang, P., Jothi, R., Hu, G* & Shi, Y.* (2014) Fip1 regulates mRNA alternative polyadenylation to promote stem cell self-renewal. EMBO J. 33: 878-889. (*Co-corresponding author)
- Featured on the cover.

13. Chan, SL., Huppertz, I., Yao, C., Weng, L., Moresco, JJ., Yates, JR. 3rd, Ule, J., Manley, JL. & Shi, Y. (2014) CPSF30 and Wdr33 directly bind to AAUAAA in mammalian mRNA 3’ processing. Genes & Dev. 28: 2370-2380.
- Featured on the cover.

14. Shi, Y. (2015) Two decades of RNA as I see it. RNA 21: 733-734.

15. Shi, Y. & Manley, JL. (2015) The end of the message: multiple protein-RNA interactions define the mRNA polyadenylation site. Genes & Dev. 29: 889-897.

16. Zou D, McSweeney C, Sebastian A, Reynolds DJ, Dong F, Zhou Y, Deng D, Wang Y, Liu L, Zhu J, Zou J, Shi Y, Albert I & Mao Y. (2015) A critical role of RBM8a in proliferation and differentiation of embryonic neural progenitors. Neural Dev. 10(1):18

17. Weng L, Li Y, Xie X & Shi Y (2016) Poly(A) code analyses reveal key determinants for tissue-specific mRNA alternative polyadenylation. RNA 22:1-9.

18. Movassat M, Crabb TL, Busch A Yao C, Reynolds DJ, Shi Y, Hertel KJ. (2016) Coupling between alternative polyadenylation and alternative splicing is limited to terminal introns. RNA Biol 13(7): 646-655.

19. Huang C, Shi J, Guo Y,Huang W, Huang S, Ming S, Wu X, Zhang R, Ding J, Zhao W, Jia J, Huang X, Xiang P, Shi Y*, Yao C* (2017) A snoRNA modulates mRNA 3’ end processing and the expression of a subset of mRNAs. Nucleic Acids Research
*co-corresponding authors
- Designated as a “breakthrough article” by the journal

20. Brumbaugh J., Stefano BD, Wang X, Borkent M, Forouzmand .E, Clowers KJ, Schwarz BA, Kalocsay M, Elledge S, Gygi SP, Hu G, Shi Y*, Hochedlinger K*. Nudt21 controls cell fate by connecting alternative polyadenylation to chromatin signaling. Cell (In press)
* co-corresponding authors

21. Sun Y, Zhang Y, Hamilton K, Manley JL, Shi Y, Walz T & Tong L (2017) Molecular basis for the recognition of the human AAUAAA polyadenylation signal. Proc Natl Acad Sci U S A. (in press)

22. Zhu Y, Wang X, Forouzmand E, Jeong J, Feng Q, Sowd G, Engelman A, Xie X, Hertel KJ & Shi Y (2017) Molecular mechanisms for CFIm-mediated regulation of mRNA alternative polyadenylation. Mol Cell (in press)
Grants 1. National Institute of Health (NIH R01GM090056): 2011-2015
2. American Cancer Socity (RSG-12-186): 2012-2016
The RNA Society
Graduate Programs Cellular and Molecular Biosciences

Stem Cell Biology


Research Centers Institute of Genomics and Bioinformatics
Center for Complex Biological Systems
Link to this profile http://www.faculty.uci.edu/profile.cfm?faculty_id=5699
Last updated 12/13/2017