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博士生导师
研究员

2024年获得“国家杰出青年基金”


Email: yzhang@cemps.ac.cn
个人网页:

研究方向

基因转录结构生物学

张余

个人简介

2000.09－2004.06 复旦大学 生命科学学院 学士
2004.09－2009.06 中国科学院上海药物研究所 博士
2009.10－2015.07 美国罗格斯大学Waksman研究所 博士后
2015.08－至今 中国科学院植物生理生态研究所，研究员/研究组长

研究工作

转录是RNA聚合酶（RNA Polymerase; RNAP）将遗传信息从DNA转移到RNA的过程，是遗传中心法则的关键环节。转录调控是基因差异化表达的决定性因素，决定了单细胞生物到高等动植物的几乎所有细胞层面的生命活动。因此，解析 RNAP的三维结构、工作机制与调控方式一直以来都是生命科学的前沿领域。细菌基因组由1个RNAP执行转录，真核生物的细胞核由5个RNAP执行转录（Polymerase I, II, III, IV, V；其中Pol IV, V为植物特有），线粒体基因组由1个噬菌体来源的RNAP执行转录，叶绿体基因组由1个噬菌体来源的RNAP和1个细菌来源的RNAP同时执行转录。

本研究组以噬菌体、细菌、酵母和植物的细胞核与细胞器RNAP为研究对象，探索了转录在基因表达、DNA修复、DNA甲基化过程中的重要功能和工作机制。主要的研究方向包括但不限于：

1. 细菌转录机制和调控
2. 植物细胞核基因转录机制和调控
3. 植物细胞器基因转录机制和调控
4. 植物关键性状相关的蛋白质结构解析和功能改造

主要成果

细菌与真核细胞基因转录终止机制

基因表达的关键步骤是RNA聚合酶以DNA为模板合成RNA的基因转录过程。上述过程需要RNA聚合酶在基因的5’和3’端识别信号，准确高效地起始和终止mRNA合成。正确的转录终止对RNA的稳定性、RNA聚合酶的循环利用，以及基因组的稳定性等至关重要。RNA聚合酶起始mRNA合成的机制已得到充分阐释，然而由于转录终止过程高度动态，RNA聚合酶终止mRNA合成的机制困扰领域多年。

细菌和真核生物通过不同的机制终止mRNA合成。固有转录终止（Intrinsic termination）是细菌最保守的转录终止方式。细菌RNA聚合酶转录至固有终止序列（G/C-rich的RNA发卡和紧随其后的Poly U序列）后停止mRNA合成并释放RNA。虽然固有转录终止现象40年前就被观察到，然而由于转录终止过程高度动态连续，该过程的机制尚未阐明。我们重构了细菌的体外转录终止反应，并将终止序列信号拆解，设计了三种RNA（Poly U、Poly U+部分发卡、Poly U+完整发卡）将动态的转录终止过程固定在中间状态，并分别解析了三个关键中间状态的复合物结构。我们发现Poly U序列诱导RNA聚合酶形成非活性构象，阻止NTP底物的结合从而暂停mRNA合成。随后RNA发卡折叠进RNA聚合酶内部，诱导RNA聚合酶构象变化并解离RNA。据此，我们揭示了细菌RNA聚合酶识别转录终止序列、停止转录、并解离RNA的机制。（Nature 2023；PMID: 36631609）。

真核细胞Pol II转录pre-mRNA至基因末端时，pre-mRNA被切割和多聚腺苷酸化修饰后被转运到细胞质进行翻译。而Pol II仍然往下游行进合成RNA，其转录终止依赖5’-3’RNA外切酶（酵母Rat1，哺乳动物XRN2，植物XRN3）。我们体外重构了外切酶Rat1缩短Pol II mRNA的中间态过程，并解析了上述中间状态的复合物结构。结果发现外切酶Rat1稳定结合在Pol II的RNA通道外侧，外切酶结合促使转录延伸因子解离。外切酶与Pol II的结合方式能够直接将Pol II合成的mRNA引导到外切酶催化中心。随后外切酶通过对RNA 5’端进行持续切割缩短RNA长度，并利用其对RNA切割产生牵引力破坏RNA和Pol II的相互作用，最后将RNA从Pol II 催化中心拖拽出来，解离RNA并终止Pol II 转录。我们修正了Pol II转录终止的“鱼雷”模型，我们提出Rat1鱼雷追赶上Pol II军舰之后，吸附在Pol II军舰之上，随后利用其将水解RNA释放的化学能转化成机械能将RNA从Pol II中拖拽出来。该研究成果提出了真核Pol II mRNA转录终止的工作模型，对理解真核基因转录的工作机制和调控机制具有重要意义。（Nature 2024；PMID:38538796）。

植物细胞核Pol IV/V介导基因组甲基化机制

陆生植物通过RNA介导的DNA甲基化途径（RdDM）对基因组DNA进行甲基化修饰，建立表观遗传印记。RdDM途径是植物沉默基因组转座子的主要方式，在植物生殖发育、逆境胁迫响应等过程中发挥重要作用。植物RdDM途径包含两个核心成员Pol IV和Pol V，它们是植物特有的两个RNA聚合酶，其在转座子区域合成非编码RNA，引导DNA甲基化。虽然Pol IV和Pol V已经被发现二十余年，然而其结构和工作机制尚未阐明。我们创新了基于植物悬浮细胞的内源复合物纯化方法，成功获得了低丰度的Pol IV和V完整复合物，揭示它们的独特的三维结构，并且提出了它们合成非编码RNA的特殊机制。

我们通过纯化拟南芥Pol IV的内源复合物，发现其与RDR2（以RNA为模板的RNA聚合酶）形成稳定复合物，随后解析了Pol IV-RDR2全酶和Pol IV-RDR2转录延伸复合物的冷冻电镜结构，并结合生物化学和反向遗传学方法阐明了Pol IV和RDR2协作的分子机制。我们发现Pol IV和RDR2的催化中心由内部通道相连接，据此提出 Pol IV-RDR2复合物“RNA内部传递”合成双链RNA的新颖工作机制：1）Pol IV-RDR2在基因组DNA上前进，Pol IV以双链DNA为模板合成一定长度的单链RNA；2）随后Pol IV-RDR2在基因组DNA上后退将单链RNA通过内部通道传递给RDR2；3）RDR2以单链RNA为模板合成双链RNA。该工作方式高效耦合了两个RNAP的转录过程，Pol IV将单链RNA中间产物传递给RDR2起始双链RNA合成，RDR2合成双链RNA的同时促发Pol IV转录终止，并引导Pol IV-RDR2复合物退回转录起始位点开始下一轮双链RNA合成。Pol IV-RDR2的独特工作机制保证双链RNA在基因组特定区域（如转座子序列）的高效扩增，这些双链RNA可于引导同一细胞中其他转座子位点的甲基化，也可被运输到其他组织的细胞中引导特定位点的甲基化。(Science 2021, PMID: 34941388).

在植物的RdDM通路中，Pol V转录非编码长链RNA，其与经过加工的Pol IV RNA配对后，招募DNA甲基化酶对附近的DNA区域进行甲基化修饰。Pol V由Pol II进化而来，但是其转录活性低于Pol II，其转录的基因组区域以及相互作用的调控蛋白和Pol II具有显著区别，然而由于缺乏Pol V的结构信息，Pol V转录的分子机制和调控方式尚未阐明。我们解析了Pol V和其转录因子KTF1的转录延伸复合物结构，结构显示Pol V活性中心的结构单元和Pol II具有构象差异，该差异与Pol V的较弱的转录活性相关。该研究进一步表明，Pol V具有独特的结构特征，该特征阻止其与Pol II/Pol IV的通用转录因子相互作用，从而解释了Pol V相较Pol II以及Pol IV功能的独特性。该研究结果为Pol V的转录特征提供了结构解释，为进一步研究Pol V转录延伸偶联DNA甲基化过程，理解植物基因组甲基化的工作机制打下了基础。（Nature Communications; PMID: 37253723）

植物叶绿体的转录机制

十几亿年前，蓝细菌被真核细胞吞噬，随后内共生演化为叶绿体细胞器。叶绿体中的光合作用将光能转化为化学能，吸收二氧化碳释放氧气，是地球生物圈的重要塑造者。叶绿体编码的RNA聚合酶（plant plastid-encoded RNA polymerase，PEP）在原质体到叶绿体的发育成熟过程中、以及成熟叶绿体中负责基因转录。虽然PEP被发现了三十余年，但是PEP复合物的亚基组成、工作和调控机制尚未阐明。我们创新了内源叶绿体PEP的纯化方法，并通过冷冻电镜技术解析了PEP转录复合物结构，揭示了叶绿体PEP的亚基组成、亚基组装方式、和特殊功能调控机制。结果显示PEP的核心具有典型的蓝细菌RNA聚合酶特征，位于复合物中心，另外15个真核起源的蛋白结合在PEP外围，组成了不同的功能模块，包括“支架模块”、“保护模块”、“RN模块”和“调控模块”，是目前已知最复杂的基因转录蛋白质机器。“支架模块”稳定催化模块并提供其他模块结合支架，“保护模块”通过超氧化物歧化酶功能保护PEP免受叶绿体中超氧化物攻击，“RNA模块”协助关联 RNA转录后加工，“调控模块”可能参与调控PEP的转录活性。这些功能模块由细胞核基因组编码，其在细胞质中被翻译后转运到叶绿体与PEP 的催化模块形成复合物，实现细胞核对叶绿体基因表达的控制。我们提出了RNAP聚合酶功能适应性演化的方式，为进一步探索叶绿体基因转录蛋白质机器的工作模式、理解叶绿体的基因表达调控方式、以及改造叶绿体基因表达调控网络打下了基础，为提高叶绿体光合作用效率开拓了新思路。（Cell 2024, PMID: 8428393）

 

     

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    4. 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.

    5. 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.

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    CELL专评；人民日报；中科院之声

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    8. 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. 2023, 120(16):e2219290120.

    9. 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.

    10. 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).

    11. 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.

    12. 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.
    中国科学院网站；科学网 

    13. 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.

    14. 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.

    15. 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.

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

    17. 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. 
    中国科学院网站；    中国青年报；澎湃新闻

    18. 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

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    20. 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

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    22. 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..

    23. 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.

    24. 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.

    25. 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.

    26. 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.

    27. 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.

    28. 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.

    29. 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.

    30. 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

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    34. Irina O. Vvedenskaya#, Jeremy G. Bird#, Yuanchao Zhang#, Yu Zhang, Xinfu Jiao, Ivan Barvík, Libor Krásný, 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

    35. 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.

    36. 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.

    37. 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  

    38. Jeremy G. Bird#, Yu Zhang#, Yuan Tian, Natalya Panova, Ivan Barvík, Landon Greene, Min Liu, Brian Buckley, Libor Krásný, 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.

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