Yu Zhang

Personal Profile

2015.08-present: PI, CAS center for Excellence in Molecular Plant Sciences, China

2009.10-2015.07: Postdoc, Rutgers University, USA

2004.09-2009.07: Ph.D., Shanghai Institute of Materia Medica, CAS, China

2000.09-2004.07: B.Sc. Fudan University, China

Research Work

Transcription is the first step of decoding genetic information and the most regulated step of gene expression. Transcription is also tightly coupled with other key cellular functions. The multiple-subunit RNA polymerase is the protein machinery responsible for transcription in both bacteria and eukaryotes. Our lab aims to understand the underlying mechanisms of gene transcription and transcription regulation in virus, bacteria, plants and special organelles.

Main Achievements

In prokaryotic transcription

Bacteria RNAP forms a holoenzyme with the primary σ factor to initiate transcription of most genes, while forms distinct holoenzymes with extra-cytoplasmic function (ECF) σ factors to initiate transcription of genes with cellular- or environmental-context-dependent functions. We have determined transcription initiation complexes of RNAP-σ holoenzymes in Mycobacterium tuberculosis, Escherichia coli, and Thermus thermophilus. The structures show how RNAP assembles holoenzymes with ECF σ factors, how RNAP-ECF σ holoenzyme recognizes and unwinds promoter DNA, and how RNAP-σ holoenzymes escape promoter DNA (Nat. Commun. 2019, PMID: 30858373; Nuc. Acids Res. 2019, PMID: 31131408; PNAS. 2020, PMID: 32127479).

 

Transcription factors respond to environmental signals and activate transcription of specific genes through recruiting or activating RNAP on the promoter regions of the genes. We have revealed new interaction modes of TF-RNAP-DNA and new paradigms of transcription regulation by determining transcription activation complexes comprising RNAP, promoter DNA, and transcription factors, including Escherichia coli CueR (Nat. Chem. Biol. 2021, PMID: 32989300), Bacillus subtilis BmrR (Nat. Commun. 2022, PMID: 33293519), Escherichia coli Crl (eLife 2019, PMID: 31846423), and Caulobacter crescentus GcrA (Nuc. Acids Res. 2018, 2023 PMID: 29514271; 36715319).

 

RNAP scans and facilitates repair of damaged DNA during transcription. UvrD was shown as a key coupling factor that mediates RNAP transcription and DNA repair. We mapped interaction domains among RNAP, UvrD, and other UVR proteins, and determined the crystal structures of the binary complex of RNAP-？i4 and UvrD-CTD, and the crystal structure of the binary complex of UvrB-NTD and UvrD-CTD. In collaboration with Prof. Evgeny Nudler at New York University, we show that RNA polymerase (RNAP) serves as the primary sensor of DNA damage and acts as a platform for the recruitment of NER enzymes in bacteria. (Nature 2022, PMID: 35355008)

 

Bacterial RNAP terminates mRNA transcription mainly through factor-independent termination. We presented three cryo-EM structures of E. coli factor-independent transcription termination complexes. The structures reveal that the terminator sequence induces the half-translocated conformation of the RNA-DNA hybrid to pause RNA synthesis, folding of the termination RNA hairpin in the RNA exit channel causes global conformational change to facilitate transcription bubble collapse, which leads to RNA release, and RNAP retains on DNA after releasing RNA. We depicted the order of key events during factor-independent transcription termination and proposed a new “DNA-rewinding triggered RNA release” model for intrinsic termination. (Nature 2023, PMID: 36631609)

 

Bacterial viruses (phages) sometimes hijack the transcription machinery of their bacterial hosts to express their own genes. We have determined cryo-EM structures of bacterial transcription elongation complexes comprising the bacteriophage protein P7, a master host-transcription regulator encoded by bacteriophage Xp10 of the rice pathogen Xanthomonas oryzae pv. and showed that P7 prevents transcription termination by plugging up the RNAP RNA-exit channel and impeding RNA-hairpin formation at the intrinsic terminator. Moreover, we show P7 inhibits host transcription initiation by restraining RNAP-clamp motions. (Nat. Commun. 2019, PMID: 31296855)

 

In eukaryotic transcription

 

Eukaryotic Pol II terminates mRNA transcription mainly through factor-dependent termination. We determined cryo-EM structures of the yeast Pol II pre-termination transcription complex. Our structures show that the Pol II termination factor--exoribonuclease Rat1--covers up the RNA exit channel of Pol II, guides the nascent RNA towards its active center, and rotates toward Pol II while degrading RNA. We propose that Rat1 is recruited to Pol II after cleavage of the mRNA at the polyadenylate site by displacing the elongation factors Spt4/5/6. Rat1 engages with the 5’-terminus of RNA, rotates toward Pol II while degrading it, and generates a mechanical force to pull the RNA out from Pol II active center. (Nature 2024, PMID: 38538796).

 

Eukaryotic organisms encode five multiple–subunit DNA–dependent RNA polymerases. Polymerase (Pol) I, Pol II, and Pol III are conserved in all eukaryotic organisms. However, Pol IV and Pol V are specific to land plants and are responsible for producing RNAs essential for repressing transposable elements, establishing genome imprinting, and maintaining genome integrity. We determined the cryo–EM structure of Pol IV–RDR2 transcription complexes. The structures reveal that Pol IV and RDR2 form a complex with their active sites connected by an interpolymerase channel, through which the Pol IV–generated transcript is handed over to the RDR2 active site after being backtracked, where it is used as the template for double-stranded RNA (dsRNA) synthesis. The work presents the structure of the fourth member of eukaryotic multiple–subunit RNA polymerases, the first example of 'two–polymerase' complex in all organisms, a novel interpolymerase RNA transfer mechanism, and a new transcription reaction (outputting dsRNA using genomic dsDNA as input). (Science 2021, PMID: 34941388).

 

We also determined the cryo-EM structure of KTF1-bound Pol V transcription elongation complex. The structure shows Pol V possesses a Pol II-like active center supporting its RNA extension and DNA-translocation activity. The sequence variation and conformational differences of the structural motifs in the active site of Pol V explain its inferior RNA-extension ability compared with Pol II. The KOW5 domain of KTF1 binds near the RNA exit channel of Pol V, where it can recruit Argonaute proteins to initiate the assembly of DNA methylation machinery. The above work answered the longstanding questions in the RdDM field and paved the way for further structural/mechanistic study of Pol IV and Pol V.(Nature Commun 2023, PMID: 37253723)

 

In Organelle transcription

Chloroplasts are green plastids in the cytoplasm of eukaryotic algae and plants responsible for photosynthesis. The plastid-encoded RNA polymerase (PEP) plays an essential role during chloroplast biogenesis from proplastids and functions as the predominant RNA polymerase in mature chloroplasts. The PEP-centered transcription apparatus comprises a bacterial-origin PEP core and more than a dozen eukaryotic-origin PEP-associated proteins (PAPs) encoded in the nucleus. We determined the cryo-EM structures of Nicotiana tabacum (tobacco) PEP-PAP apoenzyme and PEP-PAP transcription elongation complexes at near-atomic resolutions. Our data show the PEP core adopts a typical fold as bacterial RNAP. Fifteen PAPs bind at the periphery of the PEP core, facilitate assembling the PEP-PAP supercomplex, protect the complex from oxidation damage, and likely couple gene transcription with RNA processing. The high-resolution architecture of the chloroplast PEP provides the structural basis for further mechanistic and functional study of chloroplast transcription regulation. (Cell 2024, PMID: 8428393)

Publications

1. Chunyu Jiang#, Chengzhi Yu#, Shuyi Sun, Jiajia Lin, Mufeng Cai, Zhenquan Wei, Lingling Feng, Jianhui Li, Yan Zhang, Ke Dong, Xiaokui Guo*, Jinhong Qin* and Yu Zhang *. A new anti-CRISPR gene promotes the spread of drug-resistance plasmids in Klebsiella pneumonia. Nucleic Acids Res. 2024 Jun 18:gkae516. doi: 10.1093/nar/gkae516.

 

2. Hong-Wei Zhang, Zhang-Xi Gu, Yuan Zeng, Yu Zhang*. Mechanism of heterochromatin remodeling revealed by the DDM1 bound nucleosome structures. Structure. 2024 May 31:S0969-2126(24)00190-4. doi: 10.1016/j.str.2024.05.013.

 

3. Gang Wang#, Xi Chen#, Chengzhi Yu#, Xiaobao Shi, Wenxian Lan, Chaofeng Gao, Jun Yang, Huiling Dai, Xiaowei Zhang, Huili Zhang, Boyu Zhao, Qi Xie, Nan Yu, Zuhua He*, Yu Zhang*, Ertao Wang*. Release of a ubiquitin brake activates OsCERK1-triggered immunity in rice. Nature. 2024 May;629(8014):1158-1164.

 

4. Tian-Hao Li#, Ming-Dong Liu#, Zhan-Xi Gu, Xin Su, Yun-Hui Liu, Jin-Zhong Lin, Yu Zhang, Qing-Tao Shen*. Structures of the mumps virus polymerase complex via cryo-electron microscopy. Nat Commun. 2024 May 17;15(1):4189.

 

5. Xiaoxian Wu, Wenhui Mu, Fan Li, Shuyi Sun, Chaojun Cui, Chanhong Kim, Fei Zhou*, Yu Zhang*. Cryo-EM structures of the plant plastid-encoded RNA polymerase. Cell. 2024, 187(5):1127-1144.e21.

 

6. Yuan Zeng, Hong-Wei Zhang, Xiao-Xian Wu, Yu Zhang*. Structural basis of exoribonuclease-mediated mRNA transcription termination. Nature (2024), 628(8009):887-893

 

7. Shu-Jing Han, Yong-Liang Jiang, Lin-Lin You, Li-Qiang Shen, Xiaoxian Wu, Feng Yang, Ning Cui, Wen-Wen Kong, Hui Sun, Ke Zhou, Hui-Chao Meng, Zhi-Peng Chen, Yuxing Chen, Yu Zhang*, Cong-Zhao Zhou*. DNA looping mediates cooperative transcription activation. Nature Structural & Molecular Biology. 2024 120(16):e2219290120.

 

8. Dong-Lei Yang*, Kun Huang, Deyin Deng, Yuan Zeng, Zhenxing Wang* and Yu Zhang*. DNA-dependent RNA polymerases in plants. Plant Cell. 2023, 35(10):3641-3661.

 

9. Liqiang Shen, Giorgio Lai, Linlin You, Jing Shi, Xiaoxian Wu, Maria Puiu, Zhanxi Gu, Yu Feng*, Yulia Yuzenkova*, Yu Zhang*. An SI3-σ arch stabilizes cyanobacteria transcription initiation complex. PNAS. 2023, 120(16):e2219290120.

 

10. Hong-Wei Zhang, Kun Huang, Zhan-Xi Gu, Xiao-Xian Wu, Jia-Wei Wang & Yu Zhang*. A cryo-EM structure of KTF1-bound polymerase V transcription elongation complex. Nature Communications. 2023, 14(1):3118.

 

11. Linlin You, Expery O Omollo, Chengzhi Yu, Rachel A Mooney, Jing Shi, Liqiang Shen, Xiaoxian Wu, Aijia Wen, Dingwei He, Yuan Zeng, Yu Feng*, Robert Landick*, Yu Zhang*. Structural basis for intrinsic transcription termination. Nature, 2023, 613(7945):783-789.

 

12. Dingwei He^#, Linlin You^#, Xiaoxian Wu, Jing Shi, Aijia Wen, Zhi Yan, Wenhui Mu, Chengli Fang, Yu Feng*, Yu Zhang*. Pseudomonas aeruginosa SutA wedges RNAP lobe domain open to facilitate promoter DNA unwinding. Nature communications 2022, 13(1), 4204.

 

13. Binod K. Bharati^#, Manjunath Gowder^#, Fangfang Zheng, Khaled Alzoubi,Vladimir Svetlov, Venu Kamarthapu, Jacob W. Weaver, Vitaly Epshtein, Nikita Vasilyev, Liqiang Shen, Yu Zhang*, Evgeny Nudler*. Crucial role and mechanism of transcription-coupled DNA repair in bacteria. Nature 2022; 604, 152-159.

 

14. Yu Liu, Libing Yu, Chirangini Pukhrambam, Jared T. Winkelman, Emre Firlar, Jason T. Kaelber, Yu Zhang, Bryce E. Nickels, and Richard H. Ebright*. Structural and mechanistic basis of reiterative transcription initiation. Proceedings of the National Academy of Sciences 2022, 119, no. 5: e2115746119.

 

15. Chengli Fang, and Yu Zhang*. Bacterial MerR family transcription regulators: activationby distortion. Acta Biochimica et Biophysica Sinica 2022, 54 (1): 1-12.

 

16. Kun Huang^#, Xiao-Xian Wu^#, Cheng-Li Fang^#, Zhou-Geng Xu^#, Hong-Wei Zhang, Jian Gao, Chuan-Miao Zhou, Lin-Lin You, Zhan-Xi Gu, Wen-Hui Mu, Yu Feng*, Jia-Wei Wang*, Yu Zhang*. Pol IV and RDR2: A two-RNA-polymerase machine that produces double-stranded RNA. Science 2021;374(6575):1579-1586.

 

17. Hao Zhang, Nuo Cheng, Zhihui Li, Ling Bai, Chengli Fang, Yuwen Li, Weina Zhang, Xue Dong, Minghao Jiang, Yang Liang, Sujiang Zhang, Jianqing Mi, Jiang Zhu, Yu Zhang, Sai-Juan Chen, Yajie Zhao, Xiang-Qin Weng, Weiguo Hu*, Zhu Chen*, Jinyan Huang*, Guoyu Meng*. DNA crosslinking and recombination‐activating genes 1/2 (RAG1/2) are required for oncogenic splicing in acute lymphoblastic leukemia. Cancer Communications 2021. 41, no. 11: 1116-1136

 

18. Chengli Fang#, Steven J. Philips#, Xiaoxian Wu, Kui Chen, Jing Shi, Liqiang Shen, Juncao Xu, Yu Feng*, Thomas V. O’Halloran*, and Yu Zhang*. CueR activates transcription through a DNA distortion mechanism. Nature Chemical Biology 2021,17: 57-64.

 

19. Wenyue Dong, Xiaoqun Nie, Hong Zhu, Qingyun Liu, Kunxiong Shi, Linlin You, Yu Zhang, Hongyan Fan,Bo Yand, Chen Niu*, Liang-Dong Lyu*, Guo-Ping Zhao, Chen Yang*. Mycobacterial fatty acid catabolism is repressed by FdmR to sustain lipogenesis and virulence. Proceedings of the National Academy of Sciences 2021, no. 16: e2019305118

 

20. Kyle S. Skalenko, Lingting Li, Yuanchao Zhang, Irina O. Vvedenskaya, Jared T. Winkelman, Alexander L. Cope, Deanne M. Taylor, Premal Shaha, Richard H. Ebright, Justin B. Kinneyg, Yu Zhang, and Bryce E. Nickels*. Promoter-sequence determinants and structural basis of primer-dependent transcription initiation in Escherichia coli. Proceedings of the National Academy of Sciences 2021,118, no. 27: e2106388118

 

21. Chengli Fang^#, Linyu Li^#, Yihan Zhao, Xiaoxian Wu, Steven J. Philips, Linlin You, Mingkang Zhong, Xiaojin Shi, Thomas V. O'Halloran, Qunyi Li, Yu Zhang*. The bacterial multidrug resistance regulator BmrR distorts promoter DNA to activate transcription. Nature communications 2020, 11(1):6284.

 

22. Weifeng Huang, Yang Zhang, Liqiang Shen, Qian Fang, Qun Liu, Chenbo Gong, Chen Zhang, Yong Zhou, Cui Mao, Yongli Zhu, Jinghong Zhang, Hongping Chen, Yu Zhang, Yongjun Lin, Ralph Bock and Fei Zhou*. Accumulation of the RNA polymerase subunit RpoB depends on RNA editing by OsPPR16 and affects chloroplast development during early leaf development in rice." New Phytologist 2020, 228, no. 4: 1401-1416.

 

23. Lingting Li^#, Vadim Molodstov^#, Wei Lin, Richard Ebright*, Yu Zhang*. RNA extension drives a stepwise displacement of an initiation-factor structural module in initial transcription. PNAS 2020, 117(11): 5801-5809.

 

24. Ningning Zhuang^#, Hao Zhang^#, Lingting Li, Xiaoxian Wu, Chen Yang*, and Yu Zhang*. Crystal structures and biochemical analyses of the bacterial arginine dihydrolase ArgZ suggests a “bond rotation” catalytic mechanism. Journal of Biological Chemistry 2020, 295, 7: 2113-2124.

 

25. Fulin Wang^#, Jing Shi^#, Dingwei He^#, Bei Tong, Chao Zhang, Aijia Wen, Yu Zhang*, Yu Feng*, and Wei Lin*. Structural basis for transcription inhibition by E. coli SspA. Nucleic acids research 2020, 48: 9931-9942.

 

26. JianPing Huang^#, Chengli Fang^#, Xiaoyan Ma^#, Li Wang, Jing Yang, Jianying Luo, Yijun Yan, Yu Zhang*, Sheng-Xiong Huang*. Tropane alkaloids biosynthesis involves an unusual type III polyketide synthase and non-enzymatic condensation. Nature communications 2019, 10(1): 4036.

 

27. Juncao Xu^#, Kaijie Cui^#, Liqiang Shen, Jing Shi, Lingting Li, Linlin You, Chengli Fang, Guoping Zhao*, Yu Feng*, Bei Yang*, Yu Zhang*. Crl activates transcription by stabilizing active conformation of the master stress transcription initiation factor. eLife 2019, 8, e50928.

 

28. Jing Shi^#, Aijia Wen^#, Minxing Zhao^#, Linlin You, Yu Zhang, Yu Feng*, Structural basis of σ appropriation. Nucleic Acid Research 2019, 47(17):9423-9432.

 

29. Jing Shi, Xiang Gao, Tongguan Tian, Zhaoyang Yu, Bo Gao, Aijia Wen, Linlin You, Shenghai Chang, Xing Zhang, Yu Zhang, Yu Feng*, Structural basis of Q-dependent transcription antitermination, Nature Communications 2019, 10(1): 2925

 

30. Linlin You, Jing Shi, Liqiang Shen, Lingting Li, Chengli Fang, Chengzhi Yu, Wenbo Cheng, Yu Feng*, Yu Zhang*. Structural basis for transcription antitermination at bacterial intrinsic terminator. Nature communications 2019. 10(1) :3048

 

31. Chengli Fang^#, Lingting Li^#, Liqiang Shen, Jing Shi, Sheng Wang*, Yu Feng*, Yu Zhang*. Structures and mechanism of transcription initiation by bacterial ECF factors. Nucleic Acids Research 2019, 47(13):7094-7104

 

32. Lingting Li^#, Chengli Fang^#, Ningning Zhuang, Tiantian Wang, Yu Zhang*. Structural basis for transcription initiation by bacterial ECF σ factors. Nature Communications 2019. 10(1) :1153

 

33. Irina O. Vvedenskaya^#, Jeremy G. Bird^#, Yuanchao Zhang^#, Yu Zhang, Xinfu Jiao, Ivan Barvík, Libor Krásny, Megerditch Kiledjian, Deanne M.Taylor, Richard H. Ebright*, Bryce E.Nickels*. CapZyme-Seq Comprehensively Defines Promoter-Sequence Determinants for RNA 5′ Capping with NAD⁺. Molecular Cell 2018. 70(3): 553-564

 

34. Xiaoxian Wu^#, Diane L. Haakonsen^#, Allen G. Sanderlin, Yue J, Liu, Liqiang Shen, Ningning Zhuang, Michael T. Laub*, Yu Zhang*. Structural insights into the unique mechanism of transcription activation by Caulobacter crescentus GcrA. Nucleic Acids Research 2018. 46 (6): 3245-3256.

 

35. Xiaobiao Han^#, Liqiang Shen^#, Qijun Wang, Xufeng Cen, Jin Wang, Meng Wu, Peng Li, Wei Zhao*, Yu Zhang*, and Guoping Zhao*. Cyclic AMP inhibits the activity and promotes the acetylation of acetyl-CoA synthetase through competitive binding to the ATP/AMP pocket. Journal of Biological Chemistry 2017 292: 1374-1384.

 

36. Sonia I. Maffioli^#, Yu Zhang^#, David Degen^#, Thomas Carzaniga, Giancarlo Del Gatto, Stefania Serina, Paolo Monciardini, Carlo Mazzetti, Paola Guglierame, Gianpaolo Candiani, Alina Iulia Chiriac, Giuseppe Facchetti, Petra Kaltofen, Hans-Georg Sahl, Gianni Dehò, Stefano Donadio*, and Richard H. Ebright*. Antibacterial nucleoside-analog inhibitor of bacterial RNA polymerase: pseudouridimycin. Cell 2017, 15;169(7):1240-1248.e23

 

37. Jeremy G. Bird^#, Yu Zhang^#, Yuan Tian, Natalya Panova, Ivan Barvík, Landon Greene, Min Liu, Brian Buckley, Libor Krásny, Jeehiun K. Lee, Craig D. Kaplan, Richard H. Ebright*, Bryce E. Nickels*. The mechanism of RNA 5' capping with NAD+, NADH, and desphospho-CoA. Nature 2016, 535(7612): 444-447.

 

38. Jared T Winkelman^#, Irina O Vvedenskaya^#, Yuanchao Zhang^#, Yu Zhang#, Jeremy G Bird, Deanne M Taylor, Richard L Gourse, Richard H Ebright*, Bryce E Nickels*. Multiplexed protein-DNA cross-linking: Scrunching in transcription start site selection. Science 2016, 351(6277):1090-1093

 

39. Yu Zhang^#, David Degen^#, Mary X Ho^#, Elena Sineva, Katherine Y Ebright, Yon W Ebright, Vladimir Mekler, Hanif Vahedian-Movahed, Yu Feng, Ruiheng Yin, Steve Tuske, Herbert Irschik, Rolf Jansen, Sonia Maffioli, Stefano Donadio, Eddy Arnold, Richard H Ebright*. GE23077 binds to the RNA polymerase “I” and “I+1” sites and prevents the binding of initiating nucleotides. Elife 2014, 3, e02450

 

40. Yu Zhang, Yu Feng, Sujoy Chatterjee, Steve Tuske, Mary X Ho, Eddy Arnold, Richard H Ebright*. Structural basis of transcription initiation. Science 2012, 338 (6110), 1076-1080

 

41. Yu Zhang^#, Haitao Zhang^#, Xin-gang Yao^#, Hong Shen, Jing Chen, Chenjing Li, Lili Chen, Mingyue Zheng, Jiming Ye, Lihong Hu*, Xu Shen*, Hualiang Jiang*. (+)-Rutamarin as a dual inducer of both GLUT4 translocation and expression efficiently ameliorates glucose homeostasis in insulin-resistant mice. PLOS ONE 2012, 7 (2), e31811

 

42. Yu Zhang^#, Yan Li^#, Yue-wei Guo*, Hua-liang Jiang, Xu Shen*. A sesquiterpene quinone, dysidine, from the sponge Dysidea villosa, activates the insulin pathway through inhibition of PTPases. Acta Pharmacol Sin. 2009, 30 (3), 333-345

 

43. Qiong Liu^#, Yu Zhang^#, Zhonghui Lin, Hong Shen, Lili Chen, Lihong Hu*, Hualiang Jiang*, Xu Shen*. Danshen extract 15,16-dihydrotanshinone I functions as a potential modulator against metabolic syndrome through multi-target pathways. J Steroid Biochem Mol Biol. 2010, 120 (4), 155-163.

 

44. Deju Ye^#, Yu Zhang^#, Mingfang Zheng, Xu Zhang, Xiaomin Luo, Xu Shen*, Hualiang Jiang*, Hong Liu*. Novel thiophene derivatives as PTP1B inhibitors with selectivity and cellular activity. Bioorg Med Chem 2010, 18 (5), 1773-1782

 

45. Tiancen Hu^#, Yu Zhang^#, Lianwei Li, Shuai Chen, Jing Chen, Jianping Ding, Hualiang Jiang*, Xu Shen*. Two adjacent mutations on the dimer interface of SARS coronavirus 3C-like protease cause different conformational changes in crystal structure. Virology 2009, 388 (2), 324-334