李海涛 博士

教授

1993-1997    山东大学微生物学    学士

1997-2003    中国科学院生物物理研究所    博士

2003-2010    美国纪念斯隆凯特琳癌症中心  博士后助理研究员(10/2003),

           博士后副研究员(8/2005), 高级研究科学家(11/2006)

2010-2016    清华大学医学院   副教授

2016-至今     清华大学医学院   教授

 

● 研究兴趣、领域:

表观遗传调控与修饰生物学。表观遗传调控关注染色质层面遗传信息组织与解读,具体机制涉及到组蛋白或DNA/RNA修饰、组蛋白变体、染色质重塑以及非编码RNA等。表观遗传机制在从基因表达调控到细胞命运决定等众多生命过程中发挥着重要作用。与此同时,越来越多证据揭示表观遗传调控异常会导致各种人类疾病的发生,尤其是癌症。我们主要采用结构生物学手段,并结合其它生物化学、化学生物学、细胞生物学等技术,研究表观遗传调控和修饰生物学过程中的分子识别与催化事件。此外,我们也在积极开展基于结构的修饰调控因子改造和药物发现研究。

 

● 代表性论文:

关键词:

表观遗传,基因调控,修饰生物学,结构解析,癌症,药物发现

代表性论文(*通讯作者):

研究论文

1.Zhang X, Cao R, Niu J, Yang S, Ma H, Zhao S, and Li H* (2019) Molecular basis for hierarchical histone de-β-hydroxybutyrylation by SIRT3. Cell Disc 5:35

2.Liu G, Zheng X, Guan H, Cao Y, Qu H, Kang J, Ren X, Lei J, Dong M, Li X, and Li H* (2019) Architecture of Saccharomyces cerevisiae SAGA complex. Cell Disc 5:25

3.Farrelly LA, Thompson RE, Zhao S, Lepack AE, Lyu Y, Bhanu NV, Zhang B, Loh YE, Ramakrishnan A, Vadodaria KC, Heard KJ, Erikson G, Nakadai T, Bastle RM, Lukasak BJ, Zebroski H 3rd, Alenina N, Bader M, Berton O, Roeder RG, Molina H, Gage FH, Shen L, Garcia BA, Li H, Muir TW, and Maze I* (2019) Histone serotonylation is a permissive modification that enhances TFIID binding to H3K4me3. Nature 567: 535-539

4.Mariappan A, Soni K, Schorpp K, Zhao F, Minakar A, Zheng X, Mandad S, Macheleidt I, Ramani A, Kubelka T, Dawidowski M, Golfmann K, Wason A, Yang C, Simons, J, Schmalz, HG, Hyman AA, Aneja R, Ullrich R, Urlaub H, Odenthal M, Buttner R, Li H, Sattler M, Hadian K, and Gopalakrishnan J* (2019) Inhibition of CPAP–tubulin interaction prevents proliferation of centrosome-amplified cancer cells. EMBO J 38: e99876

5.Zhao S, Cheng L, Gao Y, Zhang B, Zheng X, Wang L, Li P*, Sun Q*, andLi H* (2018) Plant HP1 protein ADCP1 links multivalent H3K9 methylation readout to heterochromatin formation. Cell Res 0:1–13

6.Li X, Li XM, Jiang Y, Liu Z, Cui Y, Fung KY, van der Beelen She, Tian G, Wang L, Shi X, Allis CD, Li H, Li Y*, Li XD* (2018) Structure-guided development of YEATS domain inhibitors by targeting π-π-π stacking. Nat Chem Biol 14:1140-1149

7.Klein BJ, Vann KR, Andrews FH, Wang WW, Zhang J, Zhang Y, Beloglazkina AA, Mi W, Li Y, Li H, Shi X, Kutateladze AG, Strahl BD, Liu WR, and Kutateladze TG* (2018) Structural insights into the π-π-π stacking mechanism and DNA-binding activity of the YEATS domain. Nat Commun 9:4574

8.Fang J, Huang Y, Mao G, Yang S, Rennert G, Gu, L, Li H, and Li GM* (2018) Cancer-driving H3G34V/R/D mutations block H3K36 methylation and H3K36me3–MutSα interaction. Proc Natl Acad Sci USA 115: 9598-9603

9.Guo J, Zhao F, Yin W, Zhu M, Hao C, Pang Y, Wu T, Wang J, Zhao D*, Li H* , and Cheng M* (2018) Design, synthesis, structure-activity relationships study and X-ray crystallography of 3-substituted-indolin-2-one-5-carboxamide derivatives as PAK4 inhibitors. Eur J Med Chem 155: 197-209

10.Hsu C, Zhao D, Shi J, Peng D, Guan H, Li Y, Huang Y, Wen H, Li W*, Li H*, and Shi X* (2018) Gas41 links histone acetylation to H2A.Z deposition and maintenance of embryonic stem cell identity. Cell Discovery 4(1), 28

11.Cao R, Zhang X, Liu X, Li Y, and Li H* (2018) Molecular basis for histidine N1 position-specific methylation by CARNMT1. Cell Res 28: 494-496

12.Hsu C, Shi J, Yuan C, Zhao D, Jiang S, Lyu J, Wang X, Li H, Wen H, Li W, and Shi X (2018) Recognition of histone acetylation by the GAS41 YEATS domain promotes H2A.Z deposition in non-small cell lung cancer. Genes Dev, 32: 58-69

13.Zhao S, Zhang B, Yang M, Zhu J, and Li H* (2018) Systematic profiling of histone readers in Arabidopsis thaliana. Cell Reports 22: 1090-1102

14.Hao C, Zhao F, Song HY, Guo J, Li X, Jiang X, Huang R, Song S, Zhang Q, Wang R, Wang K, Pang Y, Liu T, Lu T, Huang W, Wang J, Lin B, He Z, Li H* , Li F*, Zhao D*, and Cheng M* (2018) Structure-based design of 6-chloro-4-aminoquinazoline-2-carboxamide derivatives as potent and selective p21-activated kinase 4 (PAK4) inhibitors. J Med Chem 61: 265-285

15.Mi W, Guan H, Lyu J, Zhao D, Xi Y, Jiang S, Andrews FH, Wang X, Gagea M, Wen H, Tora L, Dent SYR, Kutateladze TG, Li W*, Li H* , and Shi X* (2017) YEATS2 links histone acetylation to tumorigenesis of non-small cell lung cancer. Nat Commun 8:1088

16.Li Z, Zhao D, Xiang B, and Li H* (2017) Structural and biochemical characterization of DAXX-ATRX interaction. Protein Cell  8: 762-766

17.Zhao S, Yang M, Zhou W, Zhang B, Cheng Z, Huang J. Zhang M, Wang Z, Wang R, Chen Z, Zhu J*, and Li H* (2017) Kinetic and high-throughput profiling of epigenetic interactions by 3D-carbene chip-based surface plasmon resonance imaging technology. Proc Natl Acad Sci USA 114: E7245-E7254

18.Bae N, Viviano M, Su X, Lyu J, Cheng D, Sagum C, Castellano S, Bai X, Johnson C, Khalil ML, Shen J, Chen K, Li H* , Sbardella G*, and Bedford MT* (2017) Developing Spindlin1 small molecule inhibitors using protein microarrays. Nat Chem Biol 13:750-756

19.Wan L, Wen H, Li Y, Lvu J, Xi Y, Hoshii T, Joseph J, Wang X, Loh Y, Erb MA, Souza AL, Bradner JE, Shen L, Li W, Li H#, Allis CD#*, Armstrong SA#*, and Shi X#* (2017) ENL links histone acetylation to oncogenic gene expression in AML. Nature 543, 265-269 ( #co-senior author)

20.Xiong X, Panchenko T, Yang S, Zhao S, Yan P, Zhang W, Xie W, Li Y, Zhao Y, Allis CD, and Li H* (2016) Selective recognition of histone crotonylation by double PHD fingers of MOZ and DPF2. Nat Chem Biol 12:1111-1118

21.Yang S, Zheng X, Lu C, Li G-M, Allis CD, and Li H* (2016) Molecular basis for oncohistone H3 recognition by SETD2 methyltransferase. Genes Dev 30:1611-1616

22.Li N, Li Y, Chen K, Zheng X, Shen H, Wen H, Chen T. Dhar SS, Kan P, Zhu G, Wang Z, Shi X, Lan F, Li W*, Li H* and Lee MG* (2016) ZMYND8 complexes with JARID1D to read a poised histone H3K4me1-H3K14ac signature for metastasis-linked gene repression. Mol Cell 63:470-484

23.Zheng X, Ramani A, Soni K, Gottardo M, Zheng S, Ming Gooi L, Li W, Feng S, Mariappan A, Wason A, Wildlund P, Pozniakovaky A, Poser I, Deng H, Ou G, Riparbelli MG, Callaini G, Sattler M, Hyman A, Gopalakrishnan J*, Li H* (2016) Molecular basis for CPAP-tubulin interaction in controlling centriolar and ciliary length. Nat Commun 7:11874

24.Zhang X, Zhao D, Xiong X, He Z, and Li H*(2016) Multifaceted histone H3 methylation and phosphorylation readout by the plant homeodomain (PHD) finger of human nuclear antigen Sp100C. J Biol Chem 291:12786-12798

25.Zhao D, Guan H, Zhao S, Mi W, Wen H, Li Y, Zhao Y, Allis CD, Shi X*, and Li H*(2016) YEATS2 is a selective histone crotonylation reader. Cell Research 26:629–632

26.Li Y, Sabari BR, Panchenko T, Wen H, Zhao D, Guan H, Wan L, Tang Z, Zhao Y, Roeder R. Shi X, Allis CD*, and Li H* (2016) Molecular coupling of histone crotonylation and active transcription by AF9 YEATS domain. Mol Cell 62:181-193

27.Zhao D, Zhang X, Guan H, Xiong X, Shi Xi, Deng H, and Li H* (2016) The BAH domain of BAHD1 is a histone H3K27me3 reader. Protein Cell  7: 222-226

28.Wu R, Yue Y, Zheng X, and Li H* (2015) Molecular basis for histone N-terminal methylation by NRMT1. Genes Dev 29:2337-2342

29.Kamps J, Huang J, Poater J, Xu C, Pieters B, Dong A, Min J, Sherman W, Beuming T, Bickelhaupt FM, Li H, and Mecinovic J* (2015) Chemical basis for the recognition of trimethyllysine by epigenetic reader proteins. Nat Commun 6: 8911

30.Noh K, Wang H, Kim HR, Wenderski W, Fang F, Li CH, Dewell S, Hughes SH, Melnick AM, Patel DJ, Li H* , and Allis CD* (2015) Engineering of a histone-recognition domain in Dntm3a alters the epigenetic landscape and phenotypic features of mouse ESCs. Mol Cell 59:89-103

31.Noh K, Maze I, Zhao D, Xiang B, Wenderski W, Lewis PW, Shen L, Li H* and Allis CD* (2015) ATRX tolerates activity-dependent histone H3 "methyl/phos switching" to maintain repetitive element silencing in neurons. Proc Natl Acad Sci USA 112(22): 6820-6827

32.Li Y, Wen H, Xi Y, Tanaka K, Wang H, Peng D, Ren Y, Jin Q, Dent SYR, Li W, Li H*, and Shi X* (2014) AF9 YEATS domain links histone acetylation to DOT1L-mediated H3K79 methylation. Cell 159:558-571

33.Wen H*, Li, Y, Xi Y, Jiang S, Stratton S, Peng D, Tanaka K, Ren Y, Xia Z, Wu J, Li B, Barton MC, Li W*, Li H* , and Shi X* (2014) ZMYND11 links histone H3.3K36me3 to transcription elongation and tumour suppression. Nature 507, 263-268

34.Su X, Zhu G, Ding X, Lee SY, Dou Y, Zhu B, Wu W*, and Li H* (2014) Molecular basis underlying histone H3 lysine-arginine methylation patter readout by Spin/Ssty repeats of Spindlin1. Genes Dev 28:622-636

35.Zheng X, Gooi, LM, Wason A, Gabriel E, Mehrjardi NZ, Yang Q, Zhang X, Debec A, Basiri M, Avidor-Reiss T, Pozniakovsky A, Poser I, Saric T, Hyman AA, Li H* and Gopalakrishnan J* (2014) The conserved TCP domain of Sas-4/CPAP is essential for Peri-centriolar material tethering during centrosome biogenesis. Proc Natl Acad Sci USA 111: E345-E363

36.Ratnakumar K, Duarte LF, LeRoy G, Hasson D, Smeets D, Vardabasso C, B?nisch C, Zeng T, Xiang B, Zhang DY, Li H, Wang X, Hake SB, Schermelleh L, Garcia BA, Bernstein E (2012) ATRX-mediated chromatin association of histone variant macroH2A1 regulates alpha globin expression. Gene & Dev 26(5): 433-438

37.Iwase S, Xiang B, Ghosh S, Ren T, Lewis PW, Cochrane JC, Allis CD, Picketts DJ, Patel DJ*, Li H*, Shi Y* (2011) ATRX links atypical histone methylation recognition mechanisms to human mental retardation syndrome. Nat Struct Mol Biol 18: 769-776

38.Ruthenburg AJ,Li H, Milne T, Dou Y, McGinty RK, Yuen M, Muir TW, Patel DJ and Allis CD (2011) Recognition of a Mononucleosomal Histone Modification Pattern by BPTF via Multivalent Interactions. Cell 145: 692-706

39.Wang Z, Song J, Tom M, Wang GG, Li H, Allis CD and Patel DJ (2010) Pro Isomerization in MLL1 PHD3-Bromo Cassette Connects H3K4me Readout to CyP33 and HDAC-Mediated Repression. Cell 141:1183-94

40.Xiao A,Li H, Shechter D, Ahn SH, Fabrizio LA, Erdjument-Bromage H, Ishibe-Murakami S, Wang B, Tempst P, Hofmann K, Patel DJ, Elledge SJ and Allis CD. (2009) WSTF regulates the DNA damage response of H2A.X via a novel tyrosine kinase activity. Nature 457, 57-62

41.Wang GG, Song J, Wang Z, Dormann HL, Casadio F, Li H, Luo J, Patel DJ and Allis CD (2009) Haematopoietic malignancies caused by dysregulation of a chromatin-binding PHD finger. Nature 459, 847-851

42.Wang Y, Juranek S, Li H, Sheng G, Greg SW, Tuschl T and Patel DJ (2009) Nucleation, propagation and cleavage of target RNAs in argonaute silencing complexes. Nature 461:754-61

43.Li H#, Motamedi MR#, Yip CK, Wang Z, Walz T, Patel DJ and Moazed D (2009) An alpha motif at Tas3 C terminus mediates RITS cis-spreading and promotes heterochromatic gene silencing. Mol Cell 34(2), 155-167 (#equal contribution)

44.Wang Y, Juranek S, Li H, Sheng G, Tuschl T and Patel DJ (2008) Structure of an argonaute silencing complex with a seed-containing guide DNA and target RNA duplex. Nature 456, 921-926

45.Li H, Fischle W, Wang W, Duncan EM, Liang L, Murakami-Ishibe S, Allis CD, and Patel DJ (2007) Structural basis for lower lysine methylation state-specific readout by MBT repeats of L3MBTL1 and an engineered PHD finger. Mol Cell 28, 677-691

46.Li H, Ilin S, Wang W, Duncan EM, Wysocka J, Allis, CD, and Patel DJ (2006) Molecular basis for site-specific readout of histone H3K4 trimethylation by the BPTF PHD finger of NURF. Nature 442, 91-95

 

特邀综述与图书章节:

1.Zhao S, Yue Y, Li Y and Li H* (2019) Identification and characterization of ‘readers’ for novel histone modifications. Curr Opin Chem Biol, 51:57-65

2.Zhao S, Zhang X, and Li H* (2018) Beyond histone acetylation – writing and erasing histone acylations Curr Opin Struc Biol, 53:169–177

3.赵帅,李元元,李海涛* (2018) 组蛋白修饰的化学与生物学基础(第五章)朱景德 主编 《表观遗传与精准医学》:132-157 上海交通大学出版社, ISBN 9787313184115

4.Zhao D, Li Y, Xiong X, Chen Z, and Li H* (2017) YEATS domain - a histone acylation reader in health and disease. J Mol Biol, 429:1994-2002

5.Li Y, Zhao D, Chen Z, and Li H* (2017) YEATS domain: Linking histone crotonylation to gene regulation. Transcription, 8, 9-14

6.Noh K, Allis CD*, and Li H* (2016) Reading between the lines: “ADD”-ing histone and DNA methylation marks towards a new epigenetic “sum”. ACS Chem Biol 11:554-563

7.Zhao S and Li H* (2015) Crystallography-based mechanistic insights into epigenetic regulation. Elsevier Publisher- Y. G. Zheng (ed.) Epigenetic Technological Applications:125-147

8.Li H* , Zhao S, and Patel DJ (2015) Histone recognition by tandem modules and modulation by multiple PTMs. Springer Books - Life Sciences and Biomedicine, M.-M. Zhou (ed.) Histone Recognition:149-172

9.赵帅,苏晓楠,李元元,李海涛* (2015)组蛋白甲基化的阅读器识别机制研究进展,科技导报,08:94-100

10.Wee S, Dhanak D, Li H, Armstrong SA, Copeland RA, Sims R, Goodman VL, Baylin SB, Liu XS, Tarakhovsky A, and Schweizer L* (2014) Targeting epigenetic regulators for cancer therapy. Ann NY Acad Sci 1309:30-36

11.Li Y and Li H* (2012) Many keys to push: diversifying the ‘readership’ of plant homeodomain fingers. Acta Biochim Biophys Sin 44 (1): 28-39

12.Li H# , Taverna SD#, Ruthenburg AJ#, Patel DJ, and Allis CD (2007) Readout of chromatin marks by histone-binding modules. Nat Rev Mol Cell Biol 8(12) (#equal contribution) (Poster) (http://www.nature.com/nrm/posters/histonemarks/histonemarks.pdf)

13.Ruthenburg AJ, Li H, Patel DJ, and Allis CD (2007) Multivalent engagement of chromatin modifications by linked binding modules. Nat Rev Mol Cell Biol 8(12):983-994

14.Taverna SD*#,Li H*# , Ruthenburg AJ, Allis CD, and Patel DJ* (2007) How chromatin-binding modules interpret histone modifications: lessons from professional pocket pickers. Nat Struct Mol Biol 14(11):1025-1040  (#equal contribution & *correspondence)

● 荣誉、奖励及参加学术团体的情况:

2019        中国肿瘤青年科学家奖

2019        普洛麦格细胞生物学创新奖

2017        国家杰出青年基金

2016        清华大学第十五届良师益友

2015        教育部青年长江学者

2015        第9届药明康德生命化学研究奖

2015        人类前沿科学计划青年科学家基金奖

2014        第17届茅以升北京青年科技奖

2013        清华大学学术新人奖

2012        教育部新世纪优秀人才

杂志编委:

2018-present Transcription

2018-present Clinical Epigenetics

2015-present Signal Transduction and Targeted Therapy

 

● 联系方式:

电邮: lht at tsinghua.edu.cn

电话: +86-10-62771392 (办公室)  +86-10-62796944 (实验室)

地址: 北京海淀区清华大学医学科学楼C228 (办公室)、C224/C225 (实验室)

个人主页:https://www.scopus.com/authid/detail.uri?authorId=39861627900