教育背景
1993-1997 山东大学微生物学系 学士
1997-2003 中国科学院生物物理研究所 博士
工作经历
2003-2006 美国纪念斯隆-凯特琳癌症中心 博士后
2006-2010 美国纪念斯隆-凯特琳癌症中心 高级研究科学家
2010-2016 清华大学医学院 副教授
2016-2024 清华大学医学院 教授
2024-至今 清华大学基础医学院 教授
研究领域
表观遗传与疾病。表观遗传学关注染色质层面的生命信息建立与解读，具体机制涉及组蛋白修饰与DNA甲基化、染色质重塑、组蛋白变体与分子伴侣、表观基序和非编码RNA等。表观遗传关联代谢、信号与转录，在基因表达、细胞分化、个体发育等生命过程中发挥着关键作用，是维持表型复杂多样性的关键策略。与此同时，越来越多的证据表明表观调控异常会导致各种疾病的发生，尤其是癌症。本实验室主要通过结构与生化手段，结合细胞生物学、化学生物学、多组学、人工智能等技术，研究表观遗传调控过程中的分子识别与催化事件，探究“信息-分子-信号”调控网络的复杂度，揭示其对疾病和健康的影响；同时积极开展基于结构的分子设计和药物发现，以及分子互作表征工具开发。
科学贡献
先后发现或阐明PHD、YEATS等一系列甲基化、酰基化调控元件发挥功能的分子基础，揭示出相关表观修饰事件在遗传信息解读、表观景观建立、细胞性状决定、组织稳态维持，以及肿瘤发生等生理病理过程中的作用；合作开发出基于表面等离子体共振成像技术的分子互作深度表征平台，成功开展了数个靶向抑制剂开发。迄今在包括Nature、Cell在内的国际期刊发表学术论文或图书章节110余篇，引用逾1.6万次。
荣誉奖励
2023 北京市自然科学二等奖（第一完成人）
2022 教育部长江学者特聘教授（续聘）
2021 第14届谈家桢生命科学创新奖
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 基金委国家杰出青年基金
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
代表性论文
1.Zhao F, Deng Y, Liu W, Li H* (2024) Chapter 9 – Spin repeats and human pathologies, Chromatin Readers in Health and Disease: 257-277. V35 in Translational Epigenetics, Academic Press.
2.Zhao F, Deng Y, Yang F, Yan Y, Feng F, Peng B, Gao J*, Bedford MT*, Li H* (2024) Molecular Basis for SPINDOC-Spindlin1 engagement and its role in transcriptional attenuation. J Mol Biol 436:168371.
3.Guan H, Wang P, Zhang P, Ruan C, Ou Y, Peng B, Zheng X, Lei J, Li B, Yan C*, Li H* (2023) Diverse modes of H3K36me3-guided nucleosomal deacetylation by Rpd3S. Nature 620:669-75.
4.Liu W, Yao Q, Su X, Deng Y, Yang M, Peng B, Zhao F, Du C, Zhang X, Zhu J, Wang D*, Li W*, Li H* (2023) Molecular insights into Spindlin1-HBx interplay and its impact on HBV transcription from cccDNA minichromosome. Nat Commun 14:4663.
5.Ji X, Liu W, Zhang F, Su Y, Ding Y*, Li H* (2023) H3K36me3 and H2A. Z coordinately modulate flowering time in Arabidopsis. J Genet Genomics 673-8527.
6.Zhao W, Zhou Y, Li C, Bi Y, Wang K, Ye M, Li H* (2023) Molecular basis for protein histidine N1- specific methylation of the “His-x-His” motifs by METTL9. Cell Insight 2:100090.
7.Shi Y, Liao Y, Liu Q, Ni Z, Zhang Z, Shi M, Li P*, Li H*, Rao Y* (2023) BRD4-targeting PROTAC as a unique tool to study biomolecular condensates. Cell Discov 9:1-3.
8.Song L, Yao X, Li H, Peng B, Boka AP, Liu Y, Chen G, Liu Z, Mathias KM, Xia L, Li Q, Mir M, Li Y*, Li H*, and Wan L* (2022) Hotspot mutations in the structured ENL YEATS domain link aberrant transcriptional condensates and cancer. Mol Cell 82: 4080-4098
9.Song P, Zhao F, Li D, Qu J, Yao M, Su Y, Wang H, Zhou M, Wang Y, Gao Y, Li F, Zhao D, Zhang F, Rao Y, Xia M*, Li H*, Wang J*, Cheng M* (2022) Synthesis of selective PAK4 inhibitors for lung metastasis of lung cancer and melanoma cells. Acta Pharmaceutica Sinica B 12:2905-2922
10.Farrelly LA, Zheng S, Schrode N, Topol A, Bhanu NV, Bastle RM, Ramakrishnan A, Chan JC, Cetin B, Flaherty E, Shen L, Gleason K, Tamminga CA, Garcia BA, Li H*, Brennand KJ*, Maze L* (2022) Chromatin profifiling in human neurons reveals aberrant roles for histone acetylation and BET family proteins in schizophrenia. Nat Commun 13:2195
11.Hintzen JC, Ma H, Deng H, Witecka A, Andersen SB, Drozak J, Guo H, Qian P*, Li H*, Mecinovic J* (2022) Histidine methyltransferase SETD3 methylates structurally diverse histidine mimics in actin. Protein Sci 31: e4305
12.Zheng S, Bi Y, Chen H, Gong B, Jia S, and Li H* (2021) Molecular basis for bipartite recognition of histone H3 by the PZP domain of PHF14. Nucleic Acids Res 49:8961-8973
13.Zhao S, Chuh KN, Zhang B, Dul BE, Thomson RE, Farrelly LA, Liu X, Xu N, Xue Y, Roeder RG, Maze I*, Muir TW*, and Li H* (2021) Histone H3Q5 serotonylation stabilizes H3K4 methylation and potentiates its readout. Proc Natl Acad Sci USA 118(6)e2016742118
14.Zhang M and Li H* (2021) Missing for partnership: understanding nucleosomal de novo DNA cytosine methylation by a spliced DNMT3 complex. Signal Transduct Target Ther 6, 36
15.Ren X, Zhao Y, Xue Z, Hao N, Li Y, Guo X, Wang D, Shi X, and Li H* (2021) Histone benzoylation serves as an epigenetic mark for DPF and YEATS family proteins. Nucleic Acids Res 49: 114-126
16.Jiang Y, Chen G, Li XM, Liu S, Tian G, Li Y*, Li X*, Li H* and Li XD* (2020) Selective targeting of AF9 YEATS domain by cyclopeptide inhibitors with preorganized conformation. J Am Chem Soc 142: 21450–21459
17.Zhao F, Liu Y, Su X, Lee JE, Song Y, Wang D, Ge K, Gao J, Zhang MQ, and Li H* (2020) Molecular basis for histone H3 “K4me3-K9me3/2” methylation pattern readout by Spindlin1. J Biol Chem 295: 16877-16887
18.Armache A, Yang S, Eobbins LE, Durmaz C, Daman AW, Jeong JQ, Marinez de Paz A, Ravishankar A, Arslan T, Lin S, Panchenko T, Garcia BA, Hake SB, Allis CD, Li H*, and Josefowicz SZ* (2020) Histone H3.3 phosphorylation amplifies stimulation-induced transcription. Nature 583: 852–857
19.Li Z, Zhao S, Nelakanti RV, Lin K, Wu TP, Alderman III MH, Guo C, Wang P, Zhang M, Min W, Jiang Z, Wang Y, Li H*, Xiao A* (2020) N6-methyladenine in DNA antagonizes chromatin organizer SATB1 in early development. Nature 583: 625–630
20.Zhang M, Yang S, Nelakanti R, Zhao W, Liu G, Li Z, Liu X, Wu T, Xiao A*, and Li H* (2020) Mammalian ALKBH1 serves as an N6-mA demethylase of unpairing DNA. Cell Res 30:197-210
21.Zheng Y, Zhang X, and Li H* (2020) Molecular basis for histidine N3-specific methylation of actin His73 by SETD3. Cell Disc 6, 3
22.Wang L, Gao Y, Zheng X, Liu C, Dong S, Li R, Zhang G, Wei Y, Qu H, Li Y, Allis CD, Li G, Li H*, and Li P* (2019) Histone modifications regulate chromatin compartmentalization by contributing to a phase separation mechanism. Mol Cell 76: 646-659
23.Weinberg DN, Papillon-Cavanagh S, Chen H, Yue Y, Chen X, Rajagopalan KN, Horth C, McGuire JT, Xu X, Nikbakht H, Lemiesz AE, Marchione DM, Marunde MR, Meiners MJ, Cheek MA, Keogh MC, Bareke E, Djedid A, Harutyunyan AS, Jabado N, Garcia BA, Li H, Allis CD, Majewski J, and Lu C (2019) The histone mark H3K36me2 recruits DNMT3A and shapes the intergenic DNA methylation landscape. Nature 573: 281-286
24.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
25.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
26.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
27.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, Maze I (2019). Histone serotonylation is a permissive modification that enhances TFIID binding to H3K4me3. Nature 567: 535-539
28.Zhao S, Cheng L, Gao Y, Zhang B, Zheng X, Wang L, Li P*, Sun Q*, and Li H* (2019) Plant HP1 protein ADCP1 links multivalent H3K9 methylation readout to heterochromatin formation. Cell Res 29: 54-66
29.Zhao S, Zhang X, and Li H* (2018) Beyond histone acetylation – writing and erasing histone acylations Curr Opin Struc Biol 53: 169-177
30.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
31.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
32.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, 28
33.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
34.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
35.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
36.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
37.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
38.Li Z, Zhao D, Xiang B, and Li H* (2017) Structural and biochemical characterization of DAXX-ATRX interaction. Protein Cell 8: 762-766
39.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
40.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
41.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
42.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)
43.Li Y, Zhao D, Chen Z, and Li H* (2017) YEATS domain: Linking histone crotonylation to gene regulation. Transcription, 8: 9-14
44.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
45.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
46.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
47.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
48.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
49.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
50.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
51.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
52.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
53.Wu R, Yue Y, Zheng X, and Li H* (2015) Molecular basis for histone N-terminal methylation by NRMT1. Genes Dev 29: 2337-2342
54.Zhao S and Li H* (2015) Crystallography-based mechanistic insights into epigenetic regulation. Elsevier Publisher- Y. G. Zheng (ed.) Epigenetic Technological Applications: 125-147
55.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
56.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
57.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
58.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: 6820-6827
59.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
60.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
61.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
62.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
63.Li Y and Li H* (2012) Many keys to push: diversifying the ‘readership’ of plant homeodomain fingers.
Acta Biochim Biophys Sin 44: 28-39
64.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
65.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: 155-167 (#equal contribution)
66.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: 1025-1040 (#equal contribution)
67.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
68.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)
69.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
70.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
Complete list of publications: https://scholar.google.com/citations?user=s1jNBOMAAAAJ&hl=en
