学习经历/Education

1999.09 － 2003.06 浙江大学beat365体育亚洲唯一入口 学士 生物技术

Zhejiang University B.S. Biotechnology

2003.09 － 2006.06 浙江大学beat365体育亚洲唯一入口 硕士 微生物

Zhejiang University M.S. Microbiology

2006.09 － 2012.01 美国辛辛那提大学医学院 博士 环境遗传与分子毒理

University of Cincinnati Ph.D. Environmental

Genetics and Molecular Toxicology

工作经历与任职情况/Professional Experience

2012.02 － 2018.02 美国加州大学圣地亚哥分校医学院 博士后

University California San Diego Postdoctoral Scholar

2018.02 － 至今 beat365体育亚洲唯一入口 研究员

College of Life Sciences, Wuhan University PI

主要社会兼职

细胞稳态湖北省重点实验室成员

beat365体育亚洲唯一入口RNA生物学研究所成员

Frontiers in Genetics RNA专刊客座编辑

Communications Biology, Protein & cell等杂志审稿人

SpatioTemporal Omics Consortium时空组学联盟创始成员

主要科研奖励和个人荣誉

2019　　　　　　湖北省人才项目

2009-2011　　　 Ryan　fellowship, University of Cincinnati, 美国

2009　　　　　　Carl C. Smith Graduate Student Award for Meritorious Research，美国毒理学协会

承担课程

本科生：分子生物学

主持课题项目

1.　国家自然科学基金面上项目（32171289）：R环结构动态调控在早期发育中的功能与机制研究， 2022.01-2025.12，主持

2.　国家重点研发计划"干细胞研究与器官修复"专项（2021YFA1100503）：中内胚层来源组织器官间互作对干细胞命运的转录调控，2021-2026，骨干

3.　国家自然科学基金面上项目（31970619）：H3K79甲基化调控转录延伸速率的机制及功能研究，2020.01-2023.12，主持

4.　湖北省自然科学基金重点类创新群体（2020CFA017）： RNA结合蛋白与神经系统疾病2020.03-2023.03，骨干

研究内容/Research Summary

基因表达是生成RNA与蛋白质的基础与前提，对发育、代谢等各个生命活动和疾病的发生、发展都起着核心作用，是分子生物学的重要领域，其研究对于生物医学的发展和药物开发都具有重大意义。我们主要运用分子生物学与生物化学、基因组学和生物信息学等多学科手段进行基因表达调控的机制研究。主要研究成果包括：1）发现基因转录过程中形成的特殊DNA／RNA杂合链结构R-loop与转录复合体的暂停/释放过程密切偶联，揭示了转录活性对R-loop的动态调控作用；2）发现RNA结合蛋白通过直接影响转录复合体活性或与表观遗传机制偶联实现对转录的调控作用，并发现若干RNA结合蛋白的突变干扰了转录行为，进而诱发DNA复制压力和基因组稳定性下降，最终促使癌症，如白血病的发生；3）发展了新测序方法用于研究全基因组水平的R-loop动态变化，为转录调控研究提供了新的高通量技术。

Gene expression, which includes transcription and post-transcriptional RNA processing, lays the foundation to direct diverse cellular functions in development and disease progression. Our laboratory is mainly interested in exploring the molecular basis for gene expression control in relation to disease development, such as cancer. Major projects include:

1) Inter-relationship between transcription and R-loop structure

R-loop is a three-stranded nucleic acid structure formed by hybridization of the newly transcribed RNA with the template DNA strand, leaving the non-template DNA strand displaced. Such a unique structure is widely present in the genome from bacterial to mammalian cells. R-loop is found to be involved in transcription regulation, epigenetic modulation and DNA replication, and its dysregulation is often linked to human diseases, such as cancers and neurodegenerative diseases. Our work reveals an intimate spatial-temporal association of R-loop level with transcriptional pause-release and suggests a direct role of RNA polymerase activity in regulating R-loop formation and resolution (Mol Cell,2017). Disruption of R-loop dynamics by interfering transcription pause-release is further found to cause DNA replication stress and genome instability, which is a hidden disease mechanism for RNA binding protein mutations associated leukemia (Mol Cell,2018).

2) Multi-layer regulation of gene expression by RNA binding proteins and epigenetic regulators

Transcription is a complex process that is tightly regulated by cis-regulatory elements and trans-acting factors. We have identified that RNA binding proteins, in addition to its classical roles in mediating RNA processing, often work on chromatin to fine-tune transcription, either through directly modulating RNA polymerase activity (Mol Cell,2018) or coordinating with epigenetic regulators (Mol Cell, 2016). These series of work indicate there exists a delicate network and multiple feedback mechanisms to ensure accurate transcription activity.

3) Development of new sequencing methods for functional genomics study

Fast accumulation of our knowledge in gene regulation is largely attributed to the development of functional genomics and various next-generation sequencing techniques. We have developed a new genome-wide method to map R-loop in human cells with high-resolution (Nat Protocols, 2019), which enables us to discover its role in transcription regulation and maintenance of genome integrity(Mol Cell, 2017, 2018). Further effort will be devoted to establish new methods in monitoring transcription and other molecular functions on chromatin.

发表的论文（#并列第一作者，*通讯作者）

代表性论文：

1. Wei, X., Fu, S., Li, H., Liu, Y., Wang, S., Feng, W., Yang, Y., …, Liu, L.,Chen, L.*, Xu, X.*, Fei, J-F.*, Gu Y.*. Single-cell Stereo-seq reveals induced progenitor cells involved in axolotl brain regeneration. Science, 2022, 377, 1062. Cover Story and highlighted by Science.
2. Zhang, F., and Chen, L.* Molecular Threat of Splicing Factor Mutations to Myeloid Malignancies and Potential Therapeutic Modulations. Biomedicines, 2022, 10, 1972.
3. Lin, R., Zhong, X., Zhou, Y., Geng, H., Hu, Q., Huang, Z., Hu, J., Fu, X-D., Chen, L.*, Chen, J-Y*. R-loopBase: a knowledgebase for genome-wide R-loop formation and regulation. NAR, 2022, D303-D315.
4. Xu, B., Zhang, C., Jiang, A.,… Zhou, Y., Chen, L.*, Sun, H*. Histone methyltransferase Dot1L recruits O-GlcNAc transferase to target chromatin sites to regulate histone O-GlcNAcylation. JBC, 2022, 298, 102115.
5. Zhang, M., Lai, Y., Krupalnik, V., Guo, P., Guo, X., … , Chen, L.*, Hanna, JH.*, Esteban, MA.* β-Catenin safeguards the ground state of mouse pluripotency by strengthening the robustness of the transcriptional apparatus. Sci Adv, 2020, 6: eaba1593.
6. Chen, J-Y., Zhang, X., Fu X-D.* and Chen, L.* R-ChIP for genome-wide mapping of R-loops by using inactive RNase H. Nat Protoc, 2019, 14: 1661-1685.
7. Chen, L. ^#, Chen, J-Y. ^#, Huang, Y-J. ^#, Gu, Y., Qiu, J., Qian, H., Shao, C., Hu, J., Zhang, X., He, S., Zhou, Y., Li, H., Omar A-W, Zhang, D-E*. and Fu, X-D.* Augmented R-loop is a unifying mechanism for myelodysplastic syndromes induced by high risk splicing factor mutations Mol Cell, 2018, 69: 412-425. Cover story and highlighted by Cancer Discov.
8. Chen, L. ^#, Chen, J-Y. ^#, Zhang, X., Gu, Y., Xiao, R., Shao, C., Tang, P., Qian, H., Luo, D., Li, H., Zhou, Y., Zhang, D-E. and Fu, X-D. R-ChIP using inactive RNase H reveals dynamic coupling of R-loops with transcriptional pausing at gene promoters. Mol Cell, 2017, 68: 745-757. Highlighted by Nat Rev Genet and Nat Methods.9. Wei, C.^#, Xiao, R.^#, Chen, L.^#, Cui, H.^#, Zhou, Y.^#, Xue, Y., Hu, J., Zhou, B., Tsutsui, T., Qiu, J., Li, H., and Fu, X-D. RBFox2 Binds Nascent RNA to globally regulate polycomb complex 2 targeting in mammalian genomes. Mol Cell, 2016, 62: 875-889. Highlighted by Cell Research.
10.Chen, L., Peng, Z., Meng, Q., Mongan, M., Wang, J., Sartor, M., Chen, J., Niu, L., Medvedovic, M., Kao, W., and Xia, Y. Loss of IκB kinase β promotes myofibroblast transformation and senescence through activation of the ROS-TGFβ autocrine loop. Protein Cell, 2016, 7: 338-350.

所有论文：
11. Wang, C., Xu, Q., Zhang, X., Day, D., Abraham, B., Lun, K., Chen, L., Huang, J., Ji, X. BRD2 interconnects with BRD3 to facilitate Pol II transcription initiation and elongation to prime promoters for cell differentiation. Cell Mol Life Sci, 2022, 79: 338
12. Wang, D., Wang, X., Ba, H., Ren, J., Wang, Z., Sun, H., Chen, L., Liu, C., Wang, Y., Li, J., Liu, L., Liu, T., Yang, Y., Liu, G-H., Gu, Y and Li, C. Chimeric blood vessels sustained development of the xenogeneic antler: a unique model for xenogeneic organ generation. Life Medicine, 2022, https://doi.org/10.1093/lifemedi/lnac021
13. Chen, J-Y. ^#, Lim, D-H. ^#, Chen L. ^#, Zhou Y., Zhang F., Shao C., Zhang X., Li H., Wang D., Zhang D-E., and Fu X-D. Systematic Evaluation of Different R-loop Mapping Methods: Achieving Consensus, Resolving Discrepancies and Uncovering Distinct Types of RNA:DNA Hybrids. BioRxiv, 2022, https://doi.org/10.1101/2022.02.18.480986
14. Wang, K. ^#, Wang, H. ^#, Li, C. ^#, Ying, Z., Xiao, R., Li, Q., Xiang, Y., Wang, W., Huang, J., Chen, L., Fang, P.*, Liang K.* Genomic Profiling of Native R-loops with a DNA-RNA Hybrid Recognition Sensor. Sci Adv, 2021, 7: eabe3516.
15. Zhang, C., Chen, L., Peng, D., Jiang, A., He, Y., Zeng, Y., Xie, C., Zhou, H., Luo, X., Liu, H., Chen, L., Ren, J., Wang, W., Zhao, Y. METTL3 and N6-Methyladenosine Promote Homologous Recombination-Mediated Repair of DSBs by Modulating DNA-RNA Hybrid Accumulation. Mol Cell, 2020, 79: 425-442.
16. Li, H., Wei, X., Zhou, L., Zhang, W., Wang, C., Guo, Y., Li, D., Chen, J., Liu, T., Zhang, Y., Ma, S., Wang, C., Tan, F., Xu, J., Liu, Y., Yuan, Y., Chen, L., Wang, Q., Qu, J., Shen, Y., Liu, S., Fan, G., Liu, L., Liu, X., Hou, Y., Liu, GH.*, Gu, Y.*, Xu, X.* Dynamic cell transition and immune response landscapes of axolotl limb regeneration revealed by single-cell analysis. Protein Cell, 2020, 12: 57-66.
17. Wu. T., Li, L., Jiang, X., Yang, Y., Song, Y., Chen, L., Xu, X., Shen, Y., Gu, Y. Sequencing and comparative analysis of three Chlorella genomes provide insights into strain-specific adaptation to wastewater. Sci Rep, 2019, 9: 9514.
18. Huang, Y-J., Yan, M., Chen, J-Y., Chen, L., Kim, E., Shima, T., Davis, A. G., Miyauchi, S., Stoner, S. A., Fu, X-D., Abdel-Wahab, O. I., Zhang, D-E. RUNX1 Deficiency Cooperates with SRSF2 Mutation to Further Disrupt RNA Splicing and Exacerbate Myelodysplastic Syndromes in Mouse Models. Blood, 2018, 132:1796.19. Li, X., Zhou, B., Chen, L., Gou, L., Li, H. and Fu, X-D. GRID-seq reveals the global RNA-chromatin interactome. Nat Biotechnol, 2017, 35: 940-950. Cover story and highlighted by Nat Rev Genet.
20. Chen, L., Mongan, M., Meng, Q., Wang, Q., Kao, W., and Xia, Y. Corneal wound healing requires IκB kinase β signaling in keratocytes. Plos One, 2016, 11: e0151869.
21. Qiu, J., Zhou, B., Thol, F., Zhou, Y., Chen, L., Shao, C., DeBoever, C., Hou, J., Li, H., Chaturvedi, A., Ganser, A., Bejar, R., Zhang, D-E., Fu, X-D. and Heuser, M. Distinct splicing signatures affect converged pathways in myelodysplastic syndrome patients carrying mutations in different splicing regulators. RNA, 2016, 22:1535-1549.
22. Wang, L., Zhou, Y., Xu, L., Xiao, R., Lu, X., Chen, L., Chong, J., Li, H., He, C., Fu, X-D. and Wang, D. Molecular basis for RNA polymerase II to sense DNA methylation status during elongation. Nature, 2015, 523: 621-625.
23. Komeno, Y., Huang, Y-J., Qiu, J., Lin, L., Xu, Y., Zhou, Y., Chen, L., Monterroza, D., Li, H., DeKelver, R., Yan, Ming., Fu, X-D., and Zhang, D-E. SRSF2 is essential for hematopoiesis and its myelodysplastic syndromes-related mutations dysregulate alternative pre-mRNA splicing. Mol Cell Biol, 2015, 35: 3071-3082.
24. Wang, J., Chen, L., Ko, CI., Zhang, L., Puga, A., and Xia, Y. Distinct signaling properties of mitogen-activated protein kinase kinases 4 (MKK4) and 7 (MKK7) in embryonic stem cell (ESC) differentiation. J Biol Chem, 2012, 287(4):2787-2797.
25. Chen, L., Meng, Q., Kao, W., and Xia, Y. IκB kinase β regulates epithelium migration during corneal wound healing. Plos one, 2011, 6: e16132.
26. Meng, Q., Peng, Z., Chen, L., Si, J., Dong, Z., and Xia Y. Nuclear factor-κB modulates cellular glutathione and prevents oxidative stress in cancer cells. Cancer Lett, 2010, 299: 45-53.
27. Peng, Z., Geh, E., Chen, L., Meng, Q., Fan, Y., Sartor, M., Shertzer, HG., Liu, ZG., Puga, A., and Xia, Y. Inhibitor of kappaB kinase beta regulates redox homeostasis by controlling the constitutive levels of glutathione. Mol Pharmacol, 2010, 77: 784-792.
28. Chen, L., Ovesen, JL., Puga, A., and Xia, Y. Distinct contribution of JNK and p38 to chromium cytotoxicity and inhibition of murine embryonic stem cell differentiation. Environ Health Perspect, 2009, 117: 1124-1130.
29. Mongan, M., Tan, Z., Chen, L., Peng, Z., Dietsch, M., Su, B., Leikauf, G., and Xia, Y. Mitogen-activated protein kinase kinase kinase 1 protects against nickel-induced acute lung injury. Toxicol Sci, 2008, 104: 405-411.
30. Takatori, A., Geh, E., Chen, L., Zhang, L., Meller, J., and Xia, Y. Differential transmission of MEKK1 morphogenetic signals by JNK1 and JNK2. Development, 2008, 135: 23-32.
31. Du, Z., Jin, B., Liu, W., Chen, L., and Chen, J. Highly sensitive fluorescent-labeled probes and glass slide hybridization for the detection of plant RNA viruses and a viroid. Acta Biochim Biophys Sin (Shanghai), 2007, 39: 326-334.
32. Chen, L., Chen, JS., Zhang, H., and Chen, SN. Complete nucleotide sequences of three dsRNA segments from Raphanus sativus-root cv. Yidianhong with leaf yellow edge symptoms. Arch of Virol, 2006, 151: 2077-2083.

33. Chen, L., Chen, JS., Liu, L., Yu, X., Yu, S., Fu, TZ., and Liu, WH. Complete nucleotide sequences and genome characterization of double-stranded RNA 1 and RNA 2 in the Raphanus sativus-root cv. Yidianhong. Arch of Virol, 2006, 151: 849-859.

招生招聘

热诚欢迎对功能基因组学、转录调控及相关疾病研究有兴趣的本科生、硕士／博士研究生和博士后加入。