劉清華博士
- 基本信息
- 教育經歷
- 工作經歷
- 研究概述
- 發表文章
劉清華博士
北京生命科學研究所資深研究員
Qinghua Liu, Ph.D. Investigator, NIBS, Beijing, China
Phone: 86-10-80726688
Fax: 86-10-80726689
E-mail: liuqinghua@nibs.ac.cn
2000 年理學博士美國貝勒醫學院
2000 Ph.D. Department of Biochemistry, Baylor College of Medicine, USA
1992 年理學學士武漢大學生物化學系
1992 B.S. Department of Biochemistry, Wuhan University, Wuhan, China
2018- 北京生命科學研究所資深研究員2018- 北京生命科學研究所資深研究員
2018- Investigator,National Institute of Biological Sciences,Beijing, China
201304-202103 教授（“世界一流計劃”） 日本筑波大學國際綜合睡眠醫學研究所
201304-202103 Professor，International Institute of Integrative Sleep Medicine (IIIS) University of Tsukuba, Japan
201009-201712 終身副教授? 美國德州大學西南醫學中心
201009-201712 Tenured Associate Professor， University of Texas Southwestern Medical Center, USA
200406-201008 助理教授 美國德州大學西南醫學中心
200406-201008 Assistant ProfessorUniversity of Texas Southwestern Medical Center, USA
200101-200405 博士后 美國德州大學西南醫學中心
200101-200405? Postdoctoral Fellow? University of Texas Southwestern Medical Center, USA
研究概述
對于動物而言，睡眠現象是普遍存在的。然而在生物學角度精確解析睡眠的功能及其分子機理方面，仍存在巨大的未解之謎。我們的合作者Masashi Yanagisawa博士利用基于腦電圖-肌電圖（EEG/EMG）的正向遺傳學篩選手段鑒定出有明顯睡眠異常的突變小鼠，如“嗜睡型”突變（突變基因是AMP激活的蛋白激酶SIK3）和“無夢型”突變（突變基因為陽離子通道NALCN）。通過對嗜睡型和野生型睡眠剝奪小鼠的全腦進行蛋白質組學和磷酸化蛋白質組學定量比較，我們確定了80個睡眠需求指標的磷酸化蛋白 (SNIPPs)，其磷酸化水平會隨著睡眠需求而變化。SNIPPs與SLEEPY之間的緊密關聯表明它們是SLEEPY/SIK3 激酶的潛在底物,并在下游執行著睡眠穩態調節的功能。大多數SNIPPs(~86%) 被歸類為突觸蛋白，表明突觸蛋白磷酸化與睡眠需求調節機制有關。另一方面，情緒是人類的根本特質之一，也是驅使動物行為的重要動力；例如，“老鼠怕貓”是一種由基因編碼的先天恐懼。我們與諾貝爾獎獲得者 Bruce Beutler 博士合作，首次進行“恐懼”的正向遺傳學篩選，鑒定出“恐懼型”和“無懼型”突變小鼠。其中，我們發現 TRPA1 是一種新型化學傳感器，可感受捕食者氣味，從而誘發先天恐懼（例如，寒冷）行為，并確定了一個新的腦區，該區域可調節先天恐懼引起的體溫降低行為。此外，我們最近開發了一種新型成年小鼠大腦嵌合 (ABC) 表達/敲除系統，用于體細胞遺傳學分析，該系統有助于高通量篩選睡眠/恐懼調節基因并闡明睡眠和先天恐懼的分子機制。
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.
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. Nature 612:519-27 (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. Nature 612:512-18 (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. Sleep 45: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 Neuroscience 42:5617-40 (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 Communications 12:2648 (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 Communications 12:2074 (2021)
7. T. Lou, Z. Wang, J. Ma, C-Y. Li, G. Asher, L. Cao, et al., K. Sakurai and Q. Liu, Hyper-activation of mPFC underlies specific traumatic stress-induced sleep-wake EEG disturbances. Frontier in Neuroscience 14:883 (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. Nature 558:435-439 (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 Communications 9:2041 (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. Nature 539:378-383. (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 Cell 59:807-818. PMCID4560963 (2015)
12. Paroo, X. Ye, S. Chen, and Q. Liu, Phosphorylation of the human micro-RNA generating complex mediates MAPK/Erk signaling. Cell 139:112-122 (2009)
13. Y. Liu, X. Ye, F. Jiang, C. Liang, D. Chen, J. Peng, L.N. Kinch, N.V. Grishin, and Q. Liu, C3PO, an endoribonuclease that promotes RNAi by facilitating RISC activation. Science 325:750-753 (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 the Drosophila RNAi pathway. Science 301:1921-1925. (2003) (Previewed in Cell 115: 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 Dev 14: 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 Biol 8:1300-1309 (1998). (Preview in Science 283: 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 Biology 24:20 (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 Reports 41:10 (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 Metabolism 33:1974-1987 (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 Metabolism 12:62-75 (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 Cell 63:420-432. 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 Biol 35:1952-63. 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 Chem 289: 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 Biol 185:405-417. 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. Cell 156: 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 Chem 288:723-36 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 Biol 19:824-30. 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 Metabolism 15:895-904 (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 Cell 44:502-8 (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 Biol 18:650-657 (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 Cell 41: 589-599 (2011).
35. K. Okamura, N. Robine, Y. Liu, Q. Liu, and E.C. Lai, R2D2 organizes small regulatory RNA pathways in Drosophila. Mol Cell Biol 31:884-896. 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 Biol 17:17-23 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 Biotechnol 26:933-940 (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 Dev 125:475-85 (2008)
39. X. Liu, J. Park, F. Jiang, Y. Liu, D. McKearin, and Q. Liu, Dicer-1, but not Loquacious, is critical for assembly of miRNA-induced silencing complexes. RNA 13: 2324-2329 (2007).
40. X. Ye, Z. Paroo, and Q. Liu, The functional anatomy of Drosophila microRNA-generating enzyme. J Biol Chem 282: 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 Biol 27: 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. PNAS 104: 3805-3810 (2007).
43. J. Park, X. Liu, T. Strauss, D. McKearin, and Q. Liu, The miRNA pathway intrinsically controls self-renewal of Drosophila germline stem cells. Curr Biol 17: 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. RNA 12:1514-1520 (2006).
45. F. Jiang, X. Ye, X. Liu, L. Fincher, D. McKearin, Q. Liu, Dicer-1 and R3D1-L catalyze miRNA maturation in Drosophila. Genes Dev 19: 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 Cell 6:45-59 (2004).
47. Y. Sanchez, B. A. Desany, W.J. Jones, Q. Liu, B. Wang, S.J. Elledge, Regulation of RAD53 by the ATM-like kinases MEC1 and TEL1 in yeast cell cycle checkpoint pathways. Science 271: 357-360 (1996).
Invited Review and Book Chapters：
1. Q. Liu, New advances in molecular and neural mechanisms of sleep regulation. Brain Science advances 8, 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 Neuroscience 14, 773 (2022)
3. H. Zhang, Q. Liu, Translin:TRAX complex (C3PO), a novel ribonuclease for the degradation of small RNAs. Enzymes 32, 69-82 (2012).
4. Y. Liu and Q. Liu, ATM signals miRNA biogenesis through KSRP. Molecular Cell 41: 367-8 (2011)
5. Q. Liu and Z. Paroo, Dicer’s cut and switch. Science 328:314-5 (2010).
6. Q. Liu and Z. Paroo, Biochemical and regulatory mechanisms of small RNA pathways. Annual Review Biochemistry 79: 295-319 (2010)
7. X. Ye and Q. Liu, Expression, purification, and analysis of recombinant Drosophila Dicer1 and Dicer2 enzymes. Methods Molecular Biology 442:11-27 (2008).
8. Z. Paroo, Q. Liu, X. Wang, Biochemical mechanisms of the RNA-induced silencing complex. Cell Research 17: 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 Enzymology 328: 530-549 (2000).
