Dr. Yihan Wan received her B.S. in biochemistry and molecular biology from Jilin University and then her Ph.D. in Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences. She was trained in cell biology with Dr. Xueliang Zhu, and then with Dr. Yixian Zheng at Carnegie Institution for Science, Department of Embryology. In 2015, Dr. Wan joined Dr. Daniel Larson’s lab at National Cancer Institute, National Institutes of Health. Based on the strength of Dr. Larson’s state-of-the-art technique to visualize RNA in space and time, she established a high-throughput single-molecule imaging system to record the nascent RNA dynamics in living cells. This work reveals the working mechanism of RNA polymerase and spliceosome in real-time. Currently, the primary research goal of Dr. Wan is to understand the transcriptomic nascent RNA dynamics in human cells, starting from the mechanistic behavior of individual macromolecules and proceeding to their regulation in cells and tissues.

The flow of genetic information along the central dogma is essential for the development, inheritance, and evolution of all forms of biological systems. However, the current understanding of the genetic information flow is limited at spatial and temporal dimensions. The overarching goal of our study is to elucidate this information flow (i.e., gene expression) with single-molecule spatial and temporal resolutions.

We have established a quasi-genomic platform to visualize the endogenous gene transcription and splicing behavior in real-time at a single-cell level. We found that 1) All observed human genes show bursting behavior. 2) Burst sizes are conserved, while burst frequency is gene specific. 3) Splicing is a stochastic process. This stochasticity is reflected in both enzymatic activity and splice site selection. Our study proved that the abundance and identity of mRNA molecules in a single cell is a dynamic feature.

The stringent regulation in development and the stochasticity of biomolecules seem to be a paradox. Incorporating the findings of stochastic transcription and splice site selection in the context of cell lineage commitment, we are wondering: 1) How do the sporadic transcription and stochastic splicing dynamics change during lineage commitment? 2) What are the cis-element and trans-factors regulating these processes at single-molecule resolution? 3) The single-molecule live-cell imaging system provides us a unique opportunity to trace the gene expression dynamics during cell fate decisions. Therefore, we could examine the direct effect of cis-elements and trans-factors in vivo. Can we provide a network between single-molecule polymorphism (SNP) and the nascent RNA dynamics in situ? How do the non-coding SNPs affect the transcription and splicing dynamics in development and disease?  

To answer these questions, my lab aims to focus on the following research directions:

1. To obtain a broad view of nascent RNA dynamics across the human genome.

2. To understand the cell fate decision process in the context of stochastic biological processes.

3. To investigate the working mechanism of biomolecule machineries at single molecule resolution.

4. To explore the causality between SNPs in noncoding regions with transcription and splicing dynamics. How does it related diseases, and can we provide therapies?

1. Yihan Wan, Dimitrios G. Anastasakis, Joseph Rodriguez, Murali Palangat, Prabhakar Gudla, George Zaki, Mayank Tandon, Gianluca Pegoraro, Carson C Chow, Markus Hafner, Daniel R. Larson. Dynamic imaging of nascent RNA reveals general principles of transcription dynamics and pervasive recursive splicing. Cell, 2021. 184(11): p. 2878-2895 e20.

2. Yihan Wan, Daniel R Larson. Splicing heterogeneity: separating signal from noise. Genome Biol. 2018 Jul 9;19(1):86.

3. Yihan Wan, Xiaobin Zheng, Haiyang Chen, Yuxuan Guo, Hao Jiang, Xiaonan He, Xueliang Zhu, and Yixian Zheng. Pre-mRNA splicing function of mitotic regulators links R-loop mediated DNA damage to p53-dependent tumor cell killing. J Cell Biol. 2015(209):235-246. 

4. Yihan Wan, Zhenye Yang, Jing Guo, Qiangge Zhang, Liyong Zeng, Wei Sone, Yue Xiao, Xueliang Zhu. Misfolded Gβ is recruited to cytoplasmic dynein by Nudel for efficient clearance. Cell Res. 2012 Jul;22(7):1140-54.

5. Simona Patange, David A Ball, Yihan Wan, Tatiana S Karpova, Michelle Girvan, David Levens, Daniel R Larson. MYC amplifies gene expression through global changes in transcription factor dynamics. Cell Rep 2022 Vol. 38 Issue 4 Pages 110292.

6. Liyong Zeng, Yihan Wan, Dan Li, Jing Wu, Mengle Shao, Jiong Chen, Lijian Hui, Hongbin Ji and Xueliang Zhu. The m subunit of murine translation initiation factor eIF3 maintains the integrity of the eIF3 complex and is required for embryonic development, homeostasis, and organ size control. J Biol Chem. 2013 Oct 18;288(42):30087-93.

7. Hao Jiang, Xiaonan He, Shusheng Wang, Junling Jia, Yihan Wan, Yueju Wang, Rong Zeng, John Yates III, Xueliang Zhu, Yixian Zheng. A microtubule-associated zinc finger protein, BuGZ, regulates mitotic chromosome alignment by ensuring Bub3 stability and kinetochore targeting. Dev Cell. 2014 Feb 10;28(3):268-81.