刘清华博士

清华大学生物医学交叉研究院教授，北京生命科学研究所资深研究员

Qinghua Liu, Ph.D. Professor, TIMBR, Investigator, NIBS, Beijing, China

教育经历Education

2000 年理学博士美国贝勒医学院

2000 Ph.D. Department of Biochemistry, Baylor College of Medicine, USA

1992 年理学学士武汉大学生物化学系

1992 B.S. Department of Biochemistry, Wuhan University, Wuhan, China

工作经历Professional Experience

2018- 清华大学生物医学交叉研究院教授，北京生命科学研究所资深研究员

2018- Professor, TIMBR, Investigator,National Institute of Biological Sciences, Beijing, China

201304-202103 教授（“世界一流计划”） 日本筑波大学国际综合睡眠医学研究所

201304-202103 Professor，International Institute of Integrative Sleep Medicine (IIIS) University of Tsukuba, Japan

201009-201712 终身副教授 美国德州大学西南医学中心

201009-201712 Tenured Associate Professor， University of Texas Southwestern Medical Center, USA

200406-201008 助理教授 美国德州大学西南医学中心

200406-201008 Assistant ProfessorUniversity of Texas Southwestern Medical Center, USA

200101-200405 博士后 美国德州大学西南医学中心

200101-200405 Postdoctoral Fellow University of Texas Southwestern Medical Center, USA

研究概述

对于动物而言，睡眠现象是普遍存在的。然而在生物学角度精确解析睡眠的功能及其分子机理方面，仍存在巨大的未解之谜。我们的合作者Masashi Yanagisawa博士利用基于脑电图-肌电图（EEG/EMG）的正向遗传学筛选手段鉴定出有明显睡眠异常的突变小鼠，如“嗜睡型”突变（突变基因是AMP激活的蛋白激酶SIK3）和“无梦型”突变（突变基因为阳离子通道NALCN）。通过对嗜睡型和野生型睡眠剥夺小鼠的全脑进行蛋白质组学和磷酸化蛋白质组学定量比较，我们确定了80个睡眠需求指标的磷酸化蛋白 (SNIPPs)，其磷酸化水平会随着睡眠需求而变化。SNIPPs与SLEEPY之间的紧密关联表明它们是SLEEPY/SIK3 激酶的潜在底物,并在下游执行着睡眠稳态调节的功能。大多数SNIPPs(~86%) 被归类为突触蛋白，表明突触蛋白磷酸化与睡眠需求调节机制有关。另一方面，情绪是人类的根本特质之一，也是驱使动物行为的重要动力；例如，“老鼠怕猫”是一种由基因编码的先天恐惧。我们与诺贝尔奖获得者 Bruce Beutler 博士合作，首次进行“恐惧”的正向遗传学筛选，鉴定出“恐惧型”和“无惧型”突变小鼠。其中，我们发现 TRPA1 是一种新型化学传感器，可感受捕食者气味，从而诱发先天恐惧（例如，寒冷）行为，并确定了一个新的脑区，该区域可调节先天恐惧引起的体温降低行为。此外，我们最近开发了一种新型成年小鼠大脑嵌合 (ABC) 表达/敲除系统，用于体细胞遗传学分析，该系统有助于高通量筛选睡眠/恐惧调节基因并阐明睡眠和先天恐惧的分子机制。

Sleep exists ubiquitously from invertebrates to mammals. However, the precise functions and mechanisms of sleep remain one of the biggest “black boxes” in biology. We collaborated with Dr. Masashi Yanagisawa, who has conducted a EEG/EMG-based forward-genetics “sleep” screen to identify mutant mice with strong sleep abnormalities, such as Sleepy (SIK3, an AMPK-related protein kinase) and Dreamless (NALCN, a cation channel). We performed quantitative proteomic and phosphoproteomic comparison of Sleepy and sleep-deprived wild-type mouse brains, and identified 80 sleep need index phosphoproteins (SNIPPs), whose phosphorylation states change in relation to sleep need. Preferential association between SLEEPY and SNIPPs suggest that they are potentially substrates of SLEEPY/SIK3 kinase and downstream effectors of homeostatic sleep regulation. The majority (~86%) of SNIPPs are annotated synaptic proteins, suggesting a mechanistic link between synaptic phosphoproteome and sleep need regulation. On the other hand, emotions define the essence of being human and are powerful drivers of animal behaviors; For example, “mouse is afraid of cat” is a form of innate fear that is genetically encoded. In collaboration with Nobel laureate Dr. Bruce Beutler, we conducted the first forward-genetics “fear” screen to isolate “fearful” and “fearless” mutant mice. Among these, we discovered TRPA1 as a novel chemosensor for predator odor-evoked innate fear (e.g., freezing) behaviors and identified a novel brain region that mediates innate fear-associated hypothermia. Finally, we have recently developed a novel adult brain chimeric (ABC)-expression/knockout system for somatic genetics analysis in adult mice, which facilitates high-throughput screening of sleep/fear regulatory genes and elucidation of the molecular mechanisms of sleep and innate fear.

发表文章

Representative Publications：

1. R. Zhou, G. Wang, Q. Li, D. Ju, M. Liao, J. Xu, X. Gao, S. Zhou, K. Wu, Q. Sun, Y. Guo, Z. Chen, L. Chen, et al., H. Funato, M. Yanagisawa, E. Zhang,Q. Liu, A signaling pathway for transcriptional regulation of sleep amount in mice.Nature612:519-27 (2022)

2. S.J. Kim, N. Hotta-Hirashima, F. Asano, T. Kitazono, K. Iwasaki, S. Nakata, et al.,Q. Liu, C. Miyoshi, M. Yanagisawa, H. Funato,Kinase signaling pathway regulates sleep quantity and depth through a distinct population of excitatory neurons.Nature612:512-18 (2022)

3. J. Xu, R. Zhou, G. Wang, Y. Guo, X. Gao, S. Zhou, C. Ma, L. Chen, B. Shi, H. Wang, F. Wang,Q. Liu, Regulation of sleep quantity and intensity by long and short isoforms of SLEEPY kinase.Sleep45:zsac198 (2022)

4. G. Wang, Q. Li, J. Xu, S. Zhao, R. Zhou, Z. Chen, W. Jiang, X. Gao, S. Zhou, Z.Chen, Q. Sun, C. Ma, L. Chen, B. Shi, Y. Guo, H. Wang, X.Wang, H. Li, T. Cai, Y. Wang, Z. Chen, F. Wang,Q. Liu, Somatic genetics analysis of sleep in adult mice.Journal of Neuroscience42:5617-40 (2022)

5. C. Liu, C.-Y. Lee, G. Asher, L. Cao, Y. Terakoshi, P. Cao, R. Kobayakawa, K. Kobayakawa, K. Sakurai,Q. Liu, Posterior subthalamic nucleus (PSTh) mediates innate fear-associated hypothermia in mice.Nature Communications12:2648 (2021)

6. T. Matsuo, T. Isosaka, Y.Hayashi, L. Tang, A. Doi, A. Yasuda, M. Hayashi, C.Y. Lee, L. Cao, N. Kutsuna, S. Matsunaga, T. Matsuda, I. Yao, M. Setou, D. Kanagawa, K. Higasa, M. Ikawa,Q. Liu*, R. Kobayakawa*, K. Kobayakawa*, Thiazaline-related fear stimuli orchestrate hypothermia and anti-hypoxia via sensory TRPA1 activation.Nature Communications12:2074 (2021)

7. T. Lou, Z. Wang, J. Ma, C-Y. Li, G. Asher, L. Cao, et al., K. Sakurai andQ. Liu, Hyper-activation of mPFC underlies specific traumatic stress-induced sleep-wake EEG disturbances.Frontier in Neuroscience14:883 (2020)

8. Z. Wang, J. Ma, C. Miyoshi, Y. Li, M Sato, Y. Ogawa, T. Lou, C. Ma, X. Gao, C. Lee, T. Fujiyama, X. Yang, S. Zhou, N. Hotta-Hirashima, D. Klewe-Nebenus, A. Ikkyu, M. Kakizaki, S. Kanno, L. Cao, S. Takahashi, J. Peng, Y. Yu, H. Funato, M. Yanagisawa,Q. Liu, Quantitative phosphoproteomic analysis of the molecular substrates of sleep need.Nature558:435-439 (2018)

9. Y. Wang, L. Cao, C-Y. Lee, T. Matsuo, K. Wu, G. Asher, L. Tang, T. Saitoh, J. Russell, D. Klewe-Nebenius,et al., R. Kobayakawa, K. Kobayakawa, B. Beutler,Q. Liu,Large-scale forward genetics screening identifies Trpa1 as a chemosensor for predator odor-evoked innate fear behaviors.Nature Communications9:2041 (2018)

10. H. Funato, C.Miyoshi, T. Fujiyama, T. Kanda, M. Sato, Z. Wang, J. Ma, S. Nakane, et al.,Q. Liu, K. Kume, S. Wakana, J.S. Takahashi, M. Yanagiaswa,Forward- genetics analysis of sleep in randomly mutagenized mice.Nature539:378-383. (2016)

11. C. Liang, Y. Wang, Y. Murota, X. Liu, D. Smith, M.C. Siomi,Q. Liu,TAF11 assembles RISC loading complex to enhance RNAi efficiency.Molecular Cell59:807-818. PMCID4560963 (2015)

12. Paroo, X. Ye, S. Chen, andQ. Liu,Phosphorylation of the human micro-RNA generating complex mediates MAPK/Erk signaling.Cell139:112-122 (2009)

13. Y. Liu, X. Ye, F. Jiang, C. Liang, D. Chen, J. Peng, L.N. Kinch, N.V. Grishin, andQ. Liu,C3PO, an endoribonuclease that promotes RNAi by facilitating RISC activation.Science325:750-753 (2009)

14.Q. Liu, T.A. Rand, S. Kalidas, F. Du, H. Kim, D.P. Smith, X. Wang, R2D2, a bridge between the initiation and effector steps of theDrosophilaRNAi pathway.Science301:1921-1925. (2003)(Previewed inCell115: 132-133).

15.Q. Liu, S. Guntuku, X. Cui, S. Matsuoka, D. Cortez, K. Tamai, G. Luo, S. Carattini-Rivera, F. DeMayo, A. Bradley, L.A. Donehower, S.J. Elledge, Chk1 is an essential kinase that is regulated by Atr and required for the G2/M DNA damage checkpoint.Genes Dev14: 1448-1459 (2000).

16.Q. Liu, M.Z. Li, D. Liebham, D. Cortez, S.J. Elledge, The univector plasmid-fusion system, a method for rapid construction of recombinant DNA without restriction enzymes.Curr Biol8:1300-1309 (1998).(Preview inScience283: 349, 1999)

Other Publications:

17.F. Li, J. Xu, X. Guo, Z. Li, L.i Cao, S. Liu, Y. Guo, G. Wang, et al., F. Wang,Q. Liu, F. You, Collateral cleavage of 28s rRNA by RfxCas13d causes death of mice.Genome Biology24:20 (2023)

18.B. He, H. Yu, S. Liu, H. Wan, S. Fu, S. Liu, J. Yang, Z. Zhang, H. Huang, Q. Li, F. Wang, Z. Jiang,Q. Liu,H. Jiang, Mitochondrial cristae architecture protects against mtDNA release and inflammation.Cell Reports41:10 (2022)

19.S. Liu, S. Fu, G. Wang, Y. Cao, L. Li, X. Li, J. Yang, N. Li, Y. Shan, Y. Cao, Y. Ma, M. Dong,Q. Liu, H. Jiang, Glycerol-3-phosphate biosynthesis regenerates cytosolic NAD+ to alleviate mitochondria disease.Cell Metabolism33:1974-1987 (2021)

20. K.L. Egerod, N. Petersen, P.N. Timshel, J.C. Rekling, Y. Wang,Liu Q, T.W. Schwartz, L. Gautron,Profiling of G protein-coupled receptors in vagal afferents reveals novel gut-to-brain sensing mechanisms.Molecular Metabolism12:62-75 (2018).

21.H. Liu, C. Liang, R.K. Kollipara, M. Matsui, X. Ke, B-C. Jeong, Z. Wang, K.S. Yoo, G.P. Yadav, L.N. Kinch, N.V. Grishin, Y. Nam, D.R. Corey, R. Kittler,Q.Liu,HP1BP3, a chromatin retention factor for co-transcriptional microRNA processing.Molecular Cell63:420-432. PMCID4975613 (2016)

22. J. Hanus, H. Zhang, DH. Chen, Q. Zhou, P. Jin,Q. Liu, S. Wang,Gossypol Acetic Acid Prevents Oxidative Stress-Induced Retinal Pigment Epithelial Necrosis by Regulating the FoxO3/Sestrin2 Pathway.Mol Cell Biol35:1952-63. PMCID4420921 (2015)

23. J. Hanus, H. Zhang, Z. Wang,Q. Liu, Q. Zhou, S. Wang, Induction of necrotic cell death by oxidative stress in retinal pigment epithelial cells.Cell Death Disease, 36: 2217-2228 (2015)

24. Z. Wang, S. Liu, M. Kakizaki, Y. Hirose, Y. Ishikawa, H. Funato, M. Yanagisawa, Y. Yu,Q. Liu,Orexin/Hypocretin activates mTOR complex 1 (mTORC1) via an Erk/Akt-independent and calciumstimulated lysosome v-ATPase pathway.J Biol Chem289: 31950-31959. PMCID4231673 (2014)

25. M.C. Llaguno, H. Xu, L. Shi, N. Huang, H. Zhang,Q. Liu, Q-X. Jiang,Chemically functionalized carbon films for single molecule imaging.J Struc Biol185:405-417. PMCID3990355 (2014)

26. A.L.Karamyshev , A.E.Patrick, Z.N.Karamysheva , D.S.Griesemer, H.Hudson, S.Tjon-Kon-Sang, I.Nilsson , H.Otto,Q. Liu, S.Rospert, G.V.Heijne, A.E.Johnson, P.J.Thomas,Inefficient SRP interaction with a nascent chain triggers a mRNA quality control pathway.Cell156: 146-157 (2014)

27. J. Hanus, H. Zhang, Z. Wang, Q. Liu, S. Wang, Induction of necrotic cell death by oxidative stress in retinal pigment epithelia cells.Investigative Ophthalmology and Visual Science,55 633 (2014)

28. C. Liang, K. Xiong, K.E. Szulwuch, Y. Zhang, Z. Wang, J. Peng, M. Fu, P. Jing, H.I. Suzuki,Q. Liu,Sjogren Syndrome Antigen B (SSB)/La promotes global microRNA expression by binding microRNA precursors through stem-loop recognition.J Biol Chem288:723-36 PMCID3537071 (2013)

29. J. Hanus, W. Anderson, P. Jin,Q. Liu, S. Wang, Oxidative stress-induced necrosis in RPE cells.Investigative Ophthalmology and Visual Science, 54, 5001 (2013)

30. L. Li, W. Gu, C. Liang,Q. Liu,C.C. Mello, Y. Liu,The translin-TRAX complex (C3PO) is a ribonuclease in tRNA processing.Nat Struct Mol Biol19:824-30. PMCID3414638 (2012)

31. Y. Li, L. Lin, Z. Li, X. Ye, K. Xiong, B. Aryal, Z. Xu, Z. Paroo,Q. Liu,C. He, P. Jin,Iron Homeostasis Regulates the Activity of the MicroRNA Pathway through Poly(C)-Binding Protein 2.Cell Metabolism15:895-904 (2012)

32. Y. Liu, H. Tan, H. Tian, C. Liang, S. Chen,Q. Liu,Autoantigen La promotes RNAi, antiviral response, and transposon silencing by facilitating multi-turnover RISC catalysis.Molecular Cell44:502-8 (2011).

33. X. Ye, N. Huang, Y. Liu, Z. Paroo, C. Huerta, P. Li, S. Chen,Q. Liu, H. Zhang (co-corresponding authors)，Structure of C3PO and mechanism of human RISC activation.Nat Struct Mol Biol18:650-657 (2011)

34. N. Welker, T.S. Maity, X. Ye, P.J. Aruscavage, A.A. Krauchuk,Q. Liu,and B.L. Bass，Dicer's helicase domain discriminates dsRNA termini to promote an altered reaction mode.Molecular Cell41: 589-599 (2011).

35. K. Okamura, N. Robine, Y. Liu,Q. Liu, and E.C. Lai,R2D2 organizes small regulatory RNA pathways inDrosophila.Mol Cell Biol31:884-896. PMCID3028645 (2011).

36. M. Yoda, T. Kawamata, Z. Paroo, X. Ye, S. Iwasaki,Q. Liu, and Y. Tomari,ATP-dependent human RISC assembly pathways.Nat Struct Mol Biol17:17-23 PMCID2915567 (2010).

37. G.Shan,Y.Li,J.Zhang, W.Li, K.E.Szulwach, R.Duan, M.A.Faghihi, A.M.Khalil, et al.,Q.Liu, C.Wahlestedt, C.He, P.Jin, A small molecule enhances RNA interference and promotes microRNA processing.Nat Biotechnol26:933-940 (2008)

38. S. Kalidas, C.Sanders, X.Ye, T.Strauss, M.Kuhn,Q. Liu, D. Smith,Drosophila R2D2 mediates follicle formation in somatic tissues through interactions with Dicer-1.Mech Dev125:475-85 (2008)

39. X. Liu, J. Park, F. Jiang, Y. Liu, D. McKearin, andQ. Liu, Dicer-1, but not Loquacious, is critical for assembly of miRNA-induced silencing complexes.RNA13: 2324-2329 (2007).

40. X. Ye, Z. Paroo, andQ. Liu, The functional anatomy ofDrosophilamicroRNA-generating enzyme.J Biol Chem282: 28373-28378 (2007).

41. S. Choudhary, H.C.Lee, M. Maiti, P. Cheng,Q. Liu, Y. Liu, A double-stranded RNA response program important for RNAi efficiency.Mol Cell Biol27: 3995-4005 (2007).(Cover Story).

42. K. Zaugg, Y. Su, P.T. Reilly, Y. Moolani, C.C. Cheung, R. Hakem, A. Hirao,Q. Liu, S.J. Elledge, and T.W. Mak, Cross-talk between Chk1 and Chk2 in double-mutant thymocytes.PNAS104: 3805-3810 (2007).

43. J. Park, X. Liu, T. Strauss, D. McKearin, andQ. Liu, The miRNA pathway intrinsically controls self-renewal ofDrosophilagermline stem cells.Curr Biol17: 533–538(2007).(Cover story).

44. X. Liu, F. Jiang, K. Savitha, D. Smith,Q. Liu, Dicer-2 and R2D2 coordinately bind siRNA to promote assembly of the siRISC complexes.RNA12:1514-1520 (2006).

45. F. Jiang, X. Ye, X. Liu, L. Fincher, D. McKearin,Q. Liu, Dicer-1 and R3D1-L catalyze miRNA maturation inDrosophila.Genes Dev19: 1674-1679 (2005).

46. M.L. Lam,Q. Liu, S.J. Elledge, J.M. Rosen, Haplo-insufficency for Chk1 results in a damage S phase and cell cycle mis-coordination during development.Cancer Cell6:45-59 (2004).

47. Y. Sanchez, B. A. Desany, W.J. Jones,Q. Liu, B. Wang, S.J. Elledge, Regulation ofRAD53by the ATM-like kinasesMEC1andTEL1in yeast cell cycle checkpoint pathways.Science271: 357-360 (1996).

Invited Review and Book Chapters：

1.Q. Liu, New advances in molecular and neural mechanisms of sleep regulation.Brain Science advances8, 163-164. (2022)

2. M. Lazarus, Y. Hayashi, S. Honjoh, K.E. Vogt, A. Eban-Rothschild,Q. Liu, T. Sakurai. The gating and maintenance of sleep and wake: new circuits and insights.Frontiers in Neuroscience14, 773 (2022)

3. H. Zhang,Q. Liu, Translin:TRAX complex (C3PO), a novel ribonuclease for the degradation of small RNAs.Enzymes32, 69-82 (2012).

4. Y. Liu andQ. Liu, ATM signals miRNA biogenesis through KSRP.Molecular Cell41: 367-8 (2011)

5.Q. Liuand Z. Paroo, Dicer’s cut and switch.Science328:314-5 (2010).

6.Q. Liuand Z. Paroo, Biochemical and regulatory mechanisms of small RNA pathways.Annual Review Biochemistry79: 295-319 (2010)

7. X. Ye andQ. Liu, Expression, purification, and analysis of recombinant Drosophila Dicer1 and Dicer2 enzymes.Methods Molecular Biology442:11-27 (2008).

8. Z. Paroo,Q. Liu, X. Wang, Biochemical mechanisms of the RNA-induced silencing complex.Cell Research17: 187-194 (2007).

9.Q. Liu,M.Z. Li, D. Liu, S.J. Elledge, Rapid construction of recombinant DNA by the univector plasmid-fusion system.Methods Enzymology328: 530-549 (2000).