
刘肇祺LIU Zhaoqi
研究员
电子邮件: | liuzq@big.ac.cn |
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学习经历:
2006年9月-2010年7月 中国农业大学 数学与应用数学 理学学士学位
2010年9月-2015年7月 中国科学院数学与系统科学研究院 运筹学与生物信息学专业 理学博士学位
工作经历:
2021年2月至今 中国科学院北京基因组研究所(国家生物信息中心) 研究员 博士生导师
2018年9月-2020年9月 哥伦比亚大学医学院 研究助理
2015年9月-2018年8月 哥伦比亚大学医学院 博士后研究员
学术兼职:
获奖及荣誉:
中国科学院大学2022年学院级“研究生优秀课程”
超过95%的人类基因经历可变剪接产生多种转录本,这是调整转录本结构和实现基因功能多样性的重要机制。相比于正常细胞,癌细胞中广泛存在剪接功能紊乱, 癌细胞中存在数十倍于基因数量的特异性剪接变体,其衍生的基因功能改变可影响所有癌症特性(cancer hallmarks)。然而,癌症转录组的研究长期专注于基因整体表达水平,忽视基因转录结构。直到近十年,癌症中剪接功能失调才逐渐受到人们的关注,其调控机制和致癌作用尚有待深入挖掘,同时领域内缺乏专门针对癌症中剪接失调的计算分析方法。由于癌症中的剪接变体数目庞大、结构功能复杂,这为系统研究提出了重大计算挑战。如何设计针对性的计算生物学方法,系统精确刻画癌细胞特异的转录剪接缺陷图谱,如何从成千上万的剪接缺陷中识别出起最关键功能作用的致癌剪接事件,从而推动临床转化应用是亟待解决的研究难点。以上这些问题均需结合数学建模、计算科学、生物实验技术等多领域的知识技术来得到解决。针对这些难点,课题组的研究总体方向紧密围绕“癌症特异性剪接功能失调对癌症发生发展和治疗耐药的作用”这一核心科学问题,通过计算建模结合实验验证的分析方法,1) 研发肿瘤剪接分析相关的原创性计算算法,2) 探索肿瘤特异剪接体在肿瘤治疗耐药和克隆演化中的关键作用,3) 发现人类癌症中可变剪接紊乱的表观调控新机制,为研究可变剪接引起的基因功能多样性在人类疾病中的重要作用提供典范。
# First Author, *Corresponding Author
1. Yue Huang#; Jing Guo#; Xueshuai Han#; Yang Zhao; Xuejing Li; Peiqi Xing; Yulou Liu; Yingxuan Sun; Song Wu; Xuan Lv; Lei Zhou; Yazhuo Zhang; Chuzhong Li*; Weiyan Xie*; Zhaoqi Liu*; Splicing diversity enhances the molecular classification of pituitary neuroendocrine tumors, Nature Communications, 2025, 16(1): 1552
2.Xinzhi Wu#; Xueshuai Han#; Haibo Zhu#; Mingxuan Li; Lei Gong; Sicheng Jing; Weiyan Xie*; Zhaoqi Liu*; Chuzhong Li*; Yazhuo Zhang*; Single-cell transcriptomics identify a novel macrophage population associated with bone invasion in pituitary neuroendocrine tumors, Journal of Experimental & Clinical Cancer Research, 2025, 44(1): 27
3. Minu Seong#; Pedro Bak‐Gordon; Zhaoqi Liu; Peter D Canoll; James L Manley*; Splicing dysregulation in glioblastoma alters the function of cell migration‐related genes, Glia, 2025, 73(2): 215-270
4.Jingru Sui#; Dan Guo; Xiao Wen; Lei Zhou; Yue Huang; Haoyu Yu; Jinyu Chen; Zhaoqi Liu*; Systematic Characterization of Splicing Dysregulation in Pan Solid Tumor Transcriptome, Advanced science, 2024, 12(4): e2405626
5.Xueshuai Han#; Jingru Sui#; Kui Nie; Yang Zhao; Xuan Lv; Jindou Xie; Leonard Tan; Rex K. H. Au-Yeung; Jiao Ma; Giorgio Inghirami; Olivier Elemento; Wayne Tam* ; Zhaoqi Liu*; Tumor evolution analysis uncovered immune-escape related mutations in relapse of diffuse large B-cell lymphoma, Leukemia, 2024, 38(10): 2276-2280
6.Xueshuai Han#; Zhaoqi Liu*; Aberrant somatic hypermutation at super-enhancer drives B cell lymphoma transformation, Genomics, Proteomics & Bioinformatics, 2024, 22(4): qzae015
7. Isaac Wakiro#; Yue Huang#; Xuejing Yang; Xueqin Xie; Hanzhi Luo; Kathryn Chang; Aspen Pierson; Emily Batchelor; Yuanming Cheng; Diu TT Nguyen; Zhaoqi Liu*; Michael G Kharas*; Rbmx Regulates YTHDC1 Nuclear Condensates to Promote Nascent Transcription in Acute Myeloid Leukemia, Blood, 2024, 144(Supplement 1): 627-627
8.Kausik Regunath#; Vitalay Fomin; Zhaoqi Liu; Pingzhang Wang; Mainul Hoque; Bin Tian; Raul Rabadan*; Carol Prives*; Systematic Characterization of p53-Regulated Long Noncoding RNAs across Human Cancers Reveals Remarkable Heterogeneity among Different Tumor Types, Molecular Cancer Research, 2024, 22(6): 555-571
9.Jian Zhang#; Jindou Xie#; Ji Huang; Xiangyang Liu; Ruihong Xu; Jonas Tholen; Wojciech P.Galej; Liang Tong; James L. Manley*; Zhaoqi Liu* ; Characterization of the SF3B1–SUGP1 interface reveals how numerous cancer mutations cause mRNA missplicing, Genes & Development, 2023, 37: 1-16
10.Song Wu#; Yue Huang#; Mochen Zhang; Zheng Gong; Guoliang Wang; Xinchang Zheng; Wenting Zong; Wei Zhao; Peiqi Xing; Rujiao Li*; Zhaoqi Liu*; Yiming Bao*; ASCancer Atlas: a comprehensive knowledgebase of alternative splicing in human cancers, Nucleic Acids Research, 2023, 51(D1): D1196-D1204
11.Nan Han#; Zhaoqi Liu*;Targeting alternative splicing in cancer immunotherapy,Frontiers in Cell and Developmental Biology, 2023, 11: 1232146
12.Quanhua Mu#; Ruichao Chai#; Bo Pang; Yingxi Yang; Hanjie Liu; Zheng Zhao; Zhaoshi Bao; Dong Song; Zhihan Zhu; Mengli Yan; Biaobin Jiang; Zongchao Mo; Jihong Tang; Jason K Sa; Hee Jin Cho; Yuzhou Chang; Kaitlin Hao Yi Chan; Danson Shek Chun Loi; Sindy Sing Ting Tam; Aden Ka Yin Chan; Angela Ruohao Wu; Zhaoqi Liu; Wai Sang Poon; Ho Keung Ng; Danny Tat Ming Chan; Antonio Iavarone*; Do-Hyun Nam*; Tao Jiang*; Jiguang Wang*; Identifying predictors of glioma evolution from longitudinal sequencing, Science translational medicine, 2023, 15(716): eadh4181
13.Hao Guo#; Jin Xu#; Peiqi Xing#; Qilong Li; Donghai Wang; Chao Tang; Bruno Palhais; Juliette Roels; Jiaxu Liu; Sa Pan; Jinyan Huang; Zhaoqi Liu; Ping Zhu; Tom Taghon; Guoliang Qing; Pieter Van Vlierberghe*; Hudan Liu*; RNA helicase DHX15 exemplifies a unique dependency in acute leukemia, Haematologica, 2023, 108(8): 2029–2043
14.Jian Zhang#; Ji Huang; Ke Xu; Peiqi Xing; Yue Huang; Zhaoqi Liu; Liang Tong; James L. Manley*; DHX15 is involved in SUGP1-mediated RNA mis-splicing by mutant SF3B1 in cancer, Proceedings of the National Academy of Sciences 2022, 119 (49) : e2216712119.
15.Yen K. Lieu#*; Zhaoqi Liu;Abdullah M. Alig; Xin Weih; Alex Pensond; Jian Zhanga; Xiuli Anh; Raul Rabadand; Azra Razab; James L. Manleya*; Siddhartha Mukherjee*; SF3B1 mutant-induced missplicing of MAP3K7 causes anemia in myelodysplastic syndromes, Proceedings of the National Academy of Sciences 2022, 119(1): e2111703119.
16.Zhaoqi Liu#*, Raul Rabadan*;Computing the role of alternative splicing in cancer, Trends in cancer, 2021,7(4): 347-358
17.Bo Liu#; Zhaoqi Liu#; Sisi Chen; Michelle Ki; Caroline Erickson; Jorge S. Reis-Filho;Benjamin H. Durham; Qing Chang; Elisa de Stanchina; Yiwei Sun; Raul Rabadan; Omar Abdel-Wahab*; Sarat Chandarlapaty* ; Mutant SF3B1 promotes AKT and NF-kB driven mammary tumorigenesis, The Journal of Clinical Investigation, 2021, 131(1): e138315
18.Camila Prieto#; Diu Nguyen#; Zhaoqi Liu; Justin Wheat; Alexendar Perez; Saroj Gourkanti; Timothy Chou; Anthony Velleca; Thomas Rohwetter; Ersilia Barin; Arthur Chow; James Taggart; Katerina Hoskova; Meera Dhodapkar; Alexandra Schurer; Trevor S Barlowe; Ly P Vu; Christina Leslie; Ulrich Steidl; Raul Rabadan*; Michael G Kharas*; Transcriptional control of CBX5 by the RNA-binding proteins RBMX and RBMXL1 maintains chromatin state in myeloid leukemia, Nature Cancer, 2021, 2(7): 741-757
19.Delin Chen#; Bo Chu#; Xin Yang; Zhaoqi Liu; Ying Jin; Ning Kon; Raul Rabadan; Xuejun Jiang; Brent R. Stockwell; Wei Gu*; iPLA2β-mediated lipid detoxification controls p53-driven ferroptosis independent of GPX4, Nature Communications, 2021,12(1): 3644
20.Mai Sato#; Andrew Walter Liebau; Zhaoqi Liu; Lizhi Liu; Raul Rabadan; Jean Gautier*; The UVSSA complex alleviates MYC-driven transcription stress, Journal of Cell Biology, 2021, 220 (2): e201807163.
21.Zhaoqi Liu#; Ioan Filip; Karen Gomez; Dewaldt Engelbrecht; Shabnum Meer; Pooja N. Lalloo;Pareen Patel; Yvonne Perner; Junfei Zhao; Jiguang Wang; Laura Pasqualucci*; Raul Rabadan*; Pascale Willem*; Genomic Characterization of HIV-Associated Plasmablastic Lymphoma Identifies Pervasive Mutations in the JAK–STAT Pathway, Blood Cancer Discovery, 2020, 1(1): 112-125
22.Zhaoqi Liu#; Akihide Yoshimi#*; Jiguang Wang; Hana Cho; Stanley Chun-Wei Lee; Michelle Ki;Lillian Bitner; Timothy Chu; Harshal Shah; Bo Liu; Anthony R. Mato; Peter Ruvolo; Giulia Fabbri; Laura Pasqualucci; Omar Abdel-Wahab; Raul Rabadan*; Mutations in the RNA Splicing Factor SF3B1Promote Tumorigenesis through MYC Stabilization, Cancer Discovery, 2020, 10(6): 806-821
23.Zhaoqi Liu#; Jian Zhang#; Yiwei Sun; Tomin E. Perea-Chamblee; James L. Manley*; Raul Rabadan*; Pan-cancer analysis identifies mutations in SUGP1 that recapitulate mutant SF3B1 splicing dysregulation, Proceedings of the National Academy of Sciences, 2020, 117(19): 10305-10312
24.Danilo Fiore#; Luca Vincenzo Cappelli#; Paul Zumbo; Jude M Phillips; Zhaoqi Liu; Shuhua Cheng; Liron Yoffe; Paola Ghione; Federica Di Maggio; Ahmet Dogan; Inna Khodos; Elisa de Stanchina; Joseph Casano;Clarisse Kayembe; Wayne Tam; Doron Betel; Robin Foa’; Leandro Cerchietti; Raul Rabadan; Steven Horwitz; David M Weinstock; Giorgio Inghirami*; A novel JAK1 mutant breast implant-associated anaplastic large cell lymphoma patient-derived xenograft fostering pre-clinical discoveries, Cancers, 2020, 12(6): 1603
25.Luis Arnes#*; Zhaoqi Liu#; Jiguang Wang#; Carlo Maurer; Irina Sagalovskiy; Marta SanchezMartin;Nikhil Bommakanti; Diana C Garofalo; Dina A Balderes; Lori Sussel; Kenneth P Olive*; Raul Rabadan *; Comprehensive characterization of compartment-specific long non-coding RNAs associated with pancreatic ductal adenocarcinoma, Gut, 2019, 68(3): 499-511
26.Suji Han#; Hyemi Shin#; Jin-Ku Lee#; Zhaoqi Liu; Raul Rabadan; Jeongwu Lee; Jihye Shin; Cheolju Lee; Heekyoung Yang; Donggeon Kim; Sung Heon Kim; Jooyeon Kim; Jeong-Woo Oh; Doo-Sik Kong; Jung-Il Lee; Ho Jun Seol; Jung Won Choi; Hyun Ju Kang*; Do-Hyun Nam*; Secretome analysis of patient-derived GBM tumor spheres identifies midkine as a potent therapeutic target, Experimental & molecular medicine, 2019, 51(12): 1-11
27.Jian Zhang#; Abdullah M Ali; Yen K Lieu; Zhaoqi Liu; Jianchao Gao;Raul Rabadan; Azra Raza; Siddhartha Mukherjee*; James L Manley*; Disease-causing mutations in SF3B1 alter splicing by disrupting interaction with SUGP1, Molecular cell , 2019, 76(1): 82-95. e7
28.Jin-Ku Lee#; Zhaoqi Liu#; Jason K. Sa#; Sang Shin#; Jiguang Wang#; Mykola Bordyuh; Hee Jin Cho; Oliver Elliott; Timothy Chu; Seung Won Choi; Daniel I. S. Rosenbloom; In-Hee Lee; Yong Jae Shin; Hyun Ju Kang; Donggeon Kim; Sun Young Kim; Moon-Hee Sim; Jusun Kim; Taehyang Lee; Yun Jee Seo; Hyemi Shin; Mijeong Lee; Sung Heon Kim; Yong-Jun Kwon; Jeong-Woo Oh; Minsuk Song; Misuk Kim;Doo-Sik Kong; Jung Won Choi; Ho Jun Seol; Jung-Il Lee; Seung Tae Kim; Joon Oh Park; Kyoung-Mee Kim; Sang-Yong Song; Jeong-Won Lee; Hee-Cheol Kim; Jeong Eon Lee; Min Gew Choi; Sung Wook Seo; Young Mog Shim; Jae Ill Zo; Byong Chang Jeong; Yeup Yoon; Gyu Ha Ryu; Nayoung K. D. Kim; Joon Seol Bae; Woong-Yang Park; Jeongwu Lee; Roel G. W. Verhaak; Antonio Iavarone; Jeeyun Lee*; Raul Rabadan*; Do-Hyun Nam*; Pharmacogenomic landscape of patient-derived tumor cells informs precision oncology therapy, Nature Genetics, 2018, 50(10): 1399-1411
29. Magdolna Djurec#; Osvaldo Graña; Albert Lee; Kevin Troulé; Elisa Espinet; Lavinia Cabras; Carolina Navas; María Teresa Blasco; Laura Martín-Díaz; Miranda Burdiel; Jing Li, Zhaoqi Liu; Mireia Vallespinós; Francisco Sanchez-Bueno; Martin R Sprick; Andreas Trumpp; Bruno Sainz; Fátima Al-Shahrour; Raul Rabadan; Carmen Guerra*; Mariano Barbacid*; Saa3 is a key mediator of the protumorigenic properties of cancer-associated fibroblasts in pancreatic tumors, Proceedings of the National Academy of Sciences, 2018, 115(6) : E1147-E1156
30.Jin-Ku Lee#; Jiguang Wang#; Jason K Sa#; Erik Ladewig#; Hae-Ock Lee; In-Hee Lee; Hyun Ju Kang; Daniel S Rosenbloom; Pablo G Camara; Zhaoqi Liu; Patrick van Nieuwenhuizen; Sang Won Jung; Seung Won Choi; Junhyung Kim; Andrew Chen; Kyu-Tae Kim; Sang Shin; Yun Jee Seo; Jin-Mi Oh; Yong Jae Shin; Chul-Kee Park; Doo-Sik Kong; Ho Jun Seol; Andrew Blumberg; Jung-Il Lee; Antonio Iavarone; Woong-Yang Park*; Raul Rabadan* & Do-Hyun Nam*; Spatiotemporal genomic architecture informs precision oncology in glioblastoma, Nature Genetics, 2017, 49(4), 594-599
31.Jiguang Wang#; Emanuela Cazzato; Erik Ladewig; Veronique Frattini; Daniel I S Rosenbloom; Sakellarios Zairis; Francesco Abate; Zhaoqi Liu; Oliver Elliott; Yong-Jae Shin; Jin-Ku Lee; In-Hee Lee; Woong-Yang Park; Marica Eoli; Andrew J Blumberg; Anna Lasorella; Do-Hyun Nam*; Gaetano Finocchiaro*; Antonio Iavarone *; Raul Rabadan*; Clonal evolution of glioblastoma under therapy, Nature Genetics, 2016, 48(7): 768-776
32.Xuemei Ning#; Zhaoqi Liu; Shihua Zhang*; Local community extraction in directed networks, Physica A: Statistical Mechanics and its Applications, 2016, 452: 258-265
33.Zhaoqi Liu#; Shihua Zhang*; Tumor characterization and stratification by integrated molecular profiles reveals essential pan-cancer features, BMC genomics, 2015,16: 1-12
34.Meng Zou#; Zhaoqi Liu; Xiang-Sun Zhang; Yong Wang*; NCC-AUC: an AUC optimization method to identify multi-biomarker panel for cancer prognosis from genomic and clinical data, Bioinformatics, 2015, 31(20): 3330-3338
35.Xiaofeng Dai#; Zhaoqi Liu; Shihua Zhang*; Over-expression of EPS15 is a favorable prognostic factor in breast cancer, Molecular bioSystems, 2015, 11(11): 2978-2985
1. 科技部,国家重点研发项目青年科学家项目, 科学数据分析自主软件研发,2023/12- 2026/11,在研,项目负责人;
2. 国家自然科学基金委员会,面上项目,泛癌基因组可变剪切调控关系的深度挖掘,2022/01- 2025/12,在研,项目负责人;
3. 北京市自然科学基金(重点研究专题),基于单细胞技术解析SF3B1 R625突变促进肿瘤发展的机制,2022/10- 2026/10,在研,课题负责人;
4. 国家重点研发计划,基于多组学的中国卵巢癌精准分型,2023/01-2025/12,在研,参与。
癌症的异质性动态演化是疾病进展、转移和耐药的根本原因。目前癌症克隆进化研究专注于基因组层面的体细胞变异不断积累,如基因突变、基因组结构变异等。相比于基因组变异,癌细胞中的异常剪接变体在数量和结构上更加丰富,其衍生的功能多样性将为肿瘤快速进化、细胞可塑适应和选择性耐药提供更有利的条件。然而,目前领域内缺乏使用转录剪接特征系统刻画癌症演化模式的数学模型和计算方法。同样,药物诱导的剪接功能改变对治疗逃逸和耐药复发的一般性作用规律有待挖掘。另外,如何将全基因组表观遗传特征与剪接缺陷联合建模,解析其在癌症中的作用是目前领域内的重要问题和研究空白,也是一个计算上的挑战。研究组聚焦癌症中的可变剪接功能紊乱,开发计算方法和建立数学模型,利用计算生物学分析手段,致力于理解癌细胞特异转录剪接功能失调对癌症发生发展和治疗耐药的作用。
主要学术成绩包括:(1)解析癌症特异性剪接缺陷的致癌作用。设计针对癌症特异剪接缺陷的计算方法,可快速有效地识别、定量和筛选癌症转录组中所有3'/5'端剪接缺陷。首次发现SF3B1突变通过MAP3K7和PPP2R5A的3'端异常剪接来激活下游致癌信号通路,并发现针对性的治疗策略(Cancer Discovery 2020, Journal of Clinical Investigation 2021)。(2)系统揭示泛癌中3'剪接缺陷发生的调控机制。设计基于泛癌分析的计算方法,识别导致3'剪接异常的所有癌症分子特征。利用人工智能计算模型精准定位癌症中引发3'剪接缺陷的核心互作剪接蛋白复合物(PNAS 2020, Genes & Development 2023)。(3)建立了首个泛癌致病性剪接缺陷知识库。总结计算方法学在癌症可变剪接失调研究中的作用,建立了首个泛癌致病性剪接缺陷知识库,提供快速检索、多维可视化和数据下载功能(Trends in Cancer 2021, Nucleic Acids Research 2023)。(4)癌症特异性转录本异常的精准诊疗研究。设计识别癌细胞中特异性表达转录组特征,并整合基因组、转录组、表观组和临床数据对其进行筛选标注的计算生物学方法,实现对恶性肿瘤的精确诊断与分群。整合生物分子网络和药-靶关系,设计计算模型预测病人的药敏反应,发现逆转耐药的分子机制。(Nature Genetics 2018,Gut 2019, Blood Cancer Discovery 2020)。
郭 丹 硕士 工程师
赵 阳 硕士 实验员
邢培琪 博士后 2021
温 潇 博士后 2021
研究生
韩学帅, 2021
黄 悦, 2022
韩 楠, 2021
吕 萱, 2021
隋静茹, 2021
周 雷, 2021
谢金豆, 2022
许瑞鸿, 2022
殷晚晴, 2023
林汉宏, 2023
宋梦怡, 2023
赵坤宇, 2023
左一帆,2023
计算预测SF3B1-SUGP1相互作用界面揭示剪接因子癌症突变的作用机制
SF3B1是癌症中最常见的剪接因子突变。我们前期发现在剪接体U2复合物中,SF3B1的热点突变会导致其与SUGP1的互作改变。但是,与癌症剪接功能紊乱相关联的SF3B1-SUGP1的具体相互作用界面未知。为了解决这个问题,我们通过AI结构建模发现SUGP1的G-patch结构域上下游两个区域与SF3B1热点突变区域之间存在紧密蛋白互作。我们通过实验证明,落于以上互作位置的任何癌症突变都会影响SF3B1-SUGP1的蛋白结合力,而且可以诱发与癌症中SF3B1突变相似的剪接缺陷。最后,我们计算预测出SF3B1-SUGP1-DHX15三个剪接因子的蛋白复合物结构,我们发现SF3B1-SUGP1的相互作用会将SUGP1的G-patch结构域完美的“挤出”,使其与DHX15互作。因此,我们的研究揭示了一个保证3’端正确剪接的重要剪接蛋白复合物,并发现这些剪接因子在癌症中的突变会通过破坏此复合物的形成来诱发3’端剪接缺陷。(GENES & DEVELOPMENT, 2023)