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生物化学与分子生物学系

张勇

经典的生物化学研究认为细胞代谢的重要功能是为细胞的基本活动提供物质基础和能量保证,而忽略了生物体代谢的信息传递作用。近年来生命科学的研究对细胞代谢的认识有了新的突破,即机体代谢的功能不仅仅是为细胞活动提供物质和能量,更为重要的是细胞代谢中的代谢产物(特别是代谢中产物小分子,intermediate metabolites)和代谢酶可能具有十分重要的信号转导功能。探讨细胞代谢与细胞活动之间的信号转导联系已成为生命科学中最具有挑战性的热点研究领域之一。因此,发现和揭示这些具有细胞信号转导功能的酶和相应的代谢小分子在调控各种生命现象中的功能与分子机制将为解释生命的起源、进化、发育和疾病发生发展等各种基本生命现象和过程的本质提供最为基本的物质和信息基础。

骨骼肌作为机体最大的代谢内分泌器官在维持机体代谢稳态平衡中起着十分重要的调控功能。更有趣的是,骨骼肌成体干细胞位于骨骼肌纤维(Myofibers)的基底膜上。基于以上结果,本课题组正在利用骨骼肌代谢作为研究系统,探讨“骨骼肌代谢微环境(metabolic niche of myofibers)对骨骼肌干细胞功能和机体整体代谢稳态调控的作用及分子机制”。这是本课题组自2003年由朱大海教授组建以来始终致力于探究的科学问题。在此研究系统下,本课题组研究的切入点是非编码RNA和小分子代谢中间产物在调控骨骼肌代谢微环境、骨骼肌干细胞功能异质性和机体代谢稳态调控中的功能及其分子机制。同时,为了更深入的揭示细胞代谢对基因表达调控的表观遗传学机制,本课题组正在利用Hi-C、RNA-Seq和ChIP-Seq等各种高通量测序和生物信息等系统性研究手段,用整合生物学的观点从染色质高级结构动态变化角度解析所研究的调控因子发挥生理和病理功能的分子机制。

本课题组有明确和具有挑战性的科学问题,前沿和成熟的技术平台和研究经费的支持 (朱大海教授作为首席科学家主持的科技部干细胞及转化研究重点专项项目“非编码 RNA 介导的染色质高级结构动态变化对骨骼肌细胞谱系命运决定的调控作用及分子机制;张勇教授主持的科技部973项目“骨骼肌与脂肪细胞转换关键因子的鉴定及功能”;朱大海教授主持的国家自然基金委重点项目“骨骼肌特异表达Linc-RAM在骨骼肌细胞谱系建立中的功能”和面上项目“代谢小分子乙酰乙酸以信号分子方式调控骨骼肌再生与骨骼肌疾病的功能与分子机制”;张勇教授主持的自然基金委项目“MyoD结合的骨骼肌特异长非编码RNA(Linc-MCD)调控MyoD功能的分子机制”;以及中国医学科学院医学与健康科技创新工程项目)。

本课题组在非编码RNA研究方面,从骨骼肌特异表达非编码RNA的系统鉴定(Nucleic Acids Res. 2009,BMC Genomics. 2010, 2011),到非编码RNA调控骨骼肌干细胞异质性功能及分子机制(Nature Commun. 2015, 2017,Cell Death Dis, 2017)已取得了一些原创性的研究成果。特别是在长非编码RNA方面,采用生物信息学方法发现鉴定了一个受MyoD调控在骨骼肌细胞中特异表达的长非编码Linc-RAM(Long intergenic ncRNA of Activator of Myogenesis), 利用Linc-RAM敲除小鼠在整体动物水平发现了Linc-RAM在调控骨骼肌细胞谱系命运决定和分化中的功能,解析了Linc-RAM通过直接结合MyoD介导表观遗传调控复合物MyoD/Baf60c/Brg1的组装进而调节肌细胞分化相关基因的表达的分子机制(Nature commun. 2017)。

在细胞代谢的调控功能与分子机制方面,本课题组首次揭示了小分子代谢中间产物乙酰乙酸作为信号分子调控骨骼肌干细胞的激活、增殖与分化的新功能和新的分子机制(J Biol Chem. 2016);更为有趣的是,骨骼肌中磷酸烯醇式丙酮酸-丙酮酸无效循环(Futile cycle)代谢途径对脂肪组织中脂肪酸代谢的调控功能,揭示了该无效循环介导的骨骼肌和脂肪组织间相互作用(Inter-organ communication)对维持小鼠整体代谢稳态的调控功能(EBioMedicine. 2016)。EBioMedicine当期发表评论文章指出:“本研究在整体动物水平上,首次发现代谢通路中的无效循环(Futile cycle)在维持机体能量代谢稳态中的调控功能及其分子机制”。同时,本课题组还首次揭示了骨骼肌分泌因子Myostatin通过激活AMPK促进糖酵解调节骨骼肌组织糖代谢(Int J Biochem Cell Biol. 2010),以及以旁分泌方式通过调控肿瘤细胞代谢的机制诱导肿瘤细胞凋亡(Cell Death Dis. 2013)。最近的研究表明, Myostatin基因敲除小鼠骨骼肌组织中表达上调的miR-30e调控酵解型肌纤维的形成和代谢(Acta Biochim Biophys Sin. 2017),可能是Myostatin调控机体代谢稳态平衡的机制之一。这些研究结果揭示了骨骼肌分泌的细胞因子在调控细胞能量代谢和疾病方面发挥非常重要的调控功能。 在Myostatin发挥功能的分子机制研究方面本课题组鉴定了三条信号转导通路(Cancer Res. 2006;J Biol Chem. 2007;Cellular Signalling,2008)。

本课题组培养的学生毕业后已分别在教学、科研和医药研究领域和企业成为教授、副教授和管理人才。欢迎具有科学研究志向的学生与博士后加盟,本研究团队将为你提供无限的个人发展空间。

Interested applicants should send her or his CV and the names of three references to the following email address: dhzhu@pumc.edu.cn or dr_zhangyong@126.com or call at 010-6529-6949, 010-65105081.


Major scientific achievement:
● Novel role of miR-431 in mediating muscle stem cell heterogeneity by targeting Pax7 in mice (Nature Communication, 2015);
● A signaling role of the intrinsic metabolite acetoacetate in accelerating muscle regeneration and ameliorating muscular dystrophy by promoting muscle stem cell functions in mice (J Biol Chem., 2016);
● Functional requirement of the identified linc-RNA, named as Linc-RAM (Long ncRNA of Activator of Myogenesis) in control of myogenic cell lineage differentiation by directly interacting with MyoD (Nature Communication, 2017);
● Dissect signaling pathways of Myostatin function in inhibiting muscle cell proliferation and inducing cancer cells apoptosis (Cancer Research 2006, J Biol Chem. 2007, Cellular Signaling, 2008, Cell Death & Diseases, 2013).

 

Briefly describe ongoing projects

● Signaling role of small metabolites in regulating muscle stem cell functions during muscle development and regeneration.

● Myofibers-secreted factors in mediating muscle stem cell heterogeneity and muscle-fat communication for maintaining whole body metabolic homeostasis.

● Long ncRNA-mediated high order chromatin structure in controlling myogenic gene expression.


Overall research goal and scientific objectives:

● Understanding the molecular mechanisms underlying regulatory roles of non-coding RNAs and small metabolites in controlling muscle stem cells functions during skeletal muscle development, regeneration and associated diseases such as DMD.

● Investigating functional roles and molecular mechanisms of myofiber-secreted factors in mediating muscle stem cell functions and muscle-fat communication for maintaining whole body metabolic homeostasis.

The long term goal is to develop new therapeutic drugs based on the muscle-secreted factors that could treat either metabolic diseases such as obesity/diabetes by controlling glucose and lipid homeostasis in the adipose tissue and the muscle itself at the whole body levels or muscle diseases such as muscular dystrophy/atrophy by enhancing functions of muscle stem cells during muscle development, regeneration and aging.


发表文章(总体引用1500多次)

1. Xiaohua Yu#, Yong Zhang#*, Tingting Li, Zhao Ma, Haixue Jia, Qian Chen, Yixia Zhao, Lili Zhai, Ran Zhong, Changyin Li, Xiaoting Zou, Jiao Meng, Antony K. Chen, Pier Lorenzo Puri, Meihong Chen, and Dahai Zhu*. Long non-coding RNA Linc-RAM enhances myogenic differentiation by interacting with MyoD. Nat Commun. 2017. Jan 16;8:14016.

2. Lili Zhai, Rimao Wu, Wanhong Han, Yong Zhang* and Dahai Zhu*. miR-127 promotes myogenic cell differentiation by targeting S1PR3. Cell Death Dis. 2017. Mar 30;8(3):e2707. doi: 10.1038/cddis.2017.128.

3. Haixue Jia#, Yixia Zhao#, Tingting Li, Yong Zhang*, Dahai Zhu*. miR-30e is negatively regulated by myostatin in skeletal muscle and is functionally related to fiber-type composition. Acta Biochim Biophys Sin. 2017. Mar 17:1-8. doi: 10.1093/abbs/gmx019. [Epub ahead of print]

4. Yue Fan, Ying Zhang, Rimao Wu, Xingming Chen, Yong Zhang*, Xiaowei Chen*, Dahai Zhu. miR-431 is involved in regulating cochlear function by targeting Eya4. BBA - Molecular Basis of Disease. 2016 Nov;1862(11):2119-2126. doi: 10.1016/j.bbadis.2016.08.015. Epub 2016 Aug 19.

5. Ping Zeng, Wanhong Han, Changyin Li, Hu Li, Dahai Zhu, Yong Zhang*, Xiaohong Liu*. miR-378 attenuates muscle regeneration by delaying satellite cell activation and differentiation in mice. Acta Biochim Biophys Sin. 2016 Sep;48(9):833-9. doi: 10.1093/abbs/gmw077. Epub 2016 Aug 25. 

6. Yong Zhang, Changyin Li, Hu Li, Yipeng Song, Yixia Zhao, Lili Zhai, Haixia Wang, Ran Zhong, Huiru Tang, and Dahai Zhu*. miR-378 Activates the Pyruvate-PEP Futile Cycle and Enhances Lipolysis to Ameliorate Obesity in Mice. EBioMedicine. 2016. Mar 11;5:93-104.

7. Xiaoting Zou, Jiao Meng, Li Li, Wanhong Han, Changyin Li, Ran Zhong, Xuexia Miao, Jun Cai, Yong Zhang* and Dahai Zhu*. Acetoacetate accelerates muscle regeneration and ameliorates muscular dystrophy in mice. J Biol Chem. 2016 Jan 29;291(5):2181-95. Epub 2015 Dec 8.

8. Rimao Wu, Hu Li, Lili Zhai, Xiaoting Zou, Jiao Meng, Ran Zhong, Changyin Li, Haixia Wang, Yong Zhang*, Dahai Zhu*. MicroRNA-431 accelerates muscle regeneration and ameliorates muscular dystrophy by targeting Pax7 in mice. Nat Commun. 2015 Jul 7;6:7713. doi: 10.1038/ncomms8713.

9. He Cheng, Audi Wang, Jiao Meng, Yong Zhang, Dahai Zhu*. Enhanced metastasis in RNF13 knockout mice is mediated by a reduction in GM-CSF levels. Protein & Cell, 2015 Oct;6(10):746-56.

10. Rimao Wu, Hu Li, Tingting Li, Yong Zhang*, Dahai Zhu*. Myostatin regulates miR-431 expression via the Ras-Mek-Erk signaling pathway. Biochem Biophys Res Commun. 2015 May 29;461(2):224-9. doi: 10.1016/j.bbrc.2015.03.150. Epub 2015 Apr 11.

11.Jiao Meng, Xiaoting Zou, Rimao Wu, Ran Zhong, Dahai Zhu* and Yong Zhang*. Accelerated Regeneration of Skeletal Muscle in RNF13-Knockout Mice is Mediated by Macrophage-Secreted IL-4/IL-6. Protein & Cell, 2014 Mar;5(3):235-247.

12. Yong Liu, He Cheng, Yuchang Zhou, Yushan Zhu, Rui Bian, Yuewen Chen, Changyin Li, Qi Ma, Qiaoxia Zheng, Yong Zhang, Haijing Jin, Xiaohui Wang, Quan Chen, Dahai Zhu*. Myostatin induces mitochondrial metabolic alteration and typical apoptosis in cancer cells. Cell Death Dis. 2013 Feb 14;4:e494.

13. Qiang Zhang, Yanfeng Li, Lei Zhang, Nan Yang, Jiao Meng, Pingping Zuo, Yong Zhang, Jie Chen, Li Wang, Xiang Gao, Dahai Zhu*. E3 ubiquitin ligase RNF13 involves spatial learning and assembly of the SNARE complex. Cell Mol Life Sci. 2013 Jan;70(1):153-65. Epub 2012 Aug 14

14. Yao Song, Jialin Xu, Yanfeng Li, Chunshi Jia, Xiaowei Ma, Lei Zhang, Xiaojie Xie, Yong Zhang, Xiang Gao, Youyi Zhang, Dahai Zhu*. Cardiac Ankyrin Repeat Protein Attenuates Cardiac Hypertrophy by Inhibition of ERK1/2 and TGF-b Signaling Pathways. PLoS One. 2012;7(12):e50436. Epub 2012 Dec 5.  

15. Tingting Li, Suya Wang, Rimao Wu, Xueya Zhou, Dahai Zhu*, Yong Zhang*. Identification of long non-protein coding RNAs in chicken skeletal muscle using next generation sequencing. Genomics, 2012 May;99(5):292-8. Epub 2012 Feb 20.

16. Tingting Li, Rimao Wu, Yong Zhang, Dahai Zhu*. A systematic analysis of the skeletal muscle miRNA transcriptome of chicken varieties with divergent skeletal muscle growth identifies novel miRNAs and differentially expressed miRNAs. BMC Genomics. 2011 Apr 13;12(1):186.

17. Li Wang, Xiao-Pan Wu, Wei Zhang, Dahai Zhu, Ying Wang, Yan-Ping Li, Yao Tian, Rong-Cheng Li, Zhuo Li, Xinlin Zhu, Jun-Hong Li, Jun Cai, Li Liu, Xiao-Ping Miao, Ying Liu, Hui Li,Evaluation of Genetic Susceptibility Loci for Chronic Hepatitis B in Chinese: Two Independent Case-Control Studies. PLoS One, 2011 Mar 8;6(3):e17608.

18. Xianglan Jin, He Cheng, Jie Chen, Dahai Zhu*. RNF13: An Emerging RING Finger Ubiquitin Ligase Important in Cell Proliferation. FEBS J. 2011 Jan;278(1):78-84. [Epub 2010 Oct 21]

19. Yuewen Chen, Jianwei Ye, Lingzhi Cao, Yong Zhang, Weibo Xia and Dahai Zhu*. Myostatin regulates glucose metabolism via the AMP-activated protein kinase pathway in skeletal muscle cells. Int J Biochem Cell Biol. 2010 Dec;42(12):2072-81. Epub 2010 Sep 29.

20. Tingting Li, Xueya Zhou, Xiaowo Wang, Dahai Zhu*, Yong Zhang*. Identification and Characterization of Human snoRNA Core Promoters. Genomics. 2010 July; 96(1): 50-56.

21. Yong Zhang, Jun Liu, Chunshi Jia, Tingting Li, Rimao Wu, Jie Wang, Ying Chen, Xiaoting Zou, Runsheng Chen, Xiu-Jie Wang, Dahai Zhu*. Systematic identification and evolutionary features of rhesus monkey small nucleolar RNAs. BMC Genomics. 2010 Jan 25;11(1):61.

22. Qiang Zhang, Kun Wang, Yong Zhang, Jiao Meng, Fang Yu, Yan Chen, Dahai Zhu*. The myostatin-induced E3 ubiquitin ligase RNF13 negatively regulates the proliferation of chicken myoblasts. FEBS J. 2010 Jan;277(2):466-76. Epub 2009 Dec 15.

23. Yong Zhang, Jie Wang, Shoujun Huang, Xiaopeng Zhu, Jun Liu, Ning Yang, Dandan Song, Rimao Wu, Wei Deng, Geir Skogerbø, Xiu-Jie Wang, Runsheng Chen, Dahai Zhu*. Systematic identification and characterization of chicken (Gallus gallus) ncRNAs. Nucleic Acids Res. 2009 Oct;37(19):6562-74. Epub 2009 Aug 31.

24. Yuewen Chen, Lingzhi Cao, Jianwei Ye, Dahai Zhu*. Upregulation of myostatin gene expression in streptozotocin-induced type 1 diabetes mice is attenuated by insulin. Biochem Biophys Res Commun, 2009 Oct 9; 388(1):112-6. Epub 2009 Jul 30.

25. Qi Zheng, Yong Zhang, Ying Chen, Ning Yang, Xiu-Jie Wang and Dahai Zhu*. Systematic identification of genes involved in divergent skeletal muscle growth rates of broiler and layer chickens. BMC Genomics, 2009 Feb 22;10:87.

26. Qiang Zhang, Yun-Xiao Meng, Lei Zhang, Jie Chen, Dahai Zhu*. RNF13 a novel RING-type ubiquitin ligase over-expressed in pancreatic cancer. Cell Research. 2009 Mar;19(3):348-57.

27. Ming Ji, Qiang Zhang, Jianwei Ye, Xueyan Wang, Wei Yang, Dahai Zhu*. Myostatin induces p300 degradation to silence cyclin D1 expression through the PI3K/PTEN/Akt pathway. Cellular Signal, 2008 Aug;20(8):1452-8. Epub 2008 Apr 1.

28. Jianwei Ye, Yong Zhang, Jialin Xu, Qiang Zhang, Dahai Zhu*. FBXO40, a gene encoding a novel muscle-specific F-box protein, is upregulated in denervation-related muscle atrophy. Gene. 2007 Dec 1;404(1-2):53-60. Epub 2007 Sep 7.

29. Wei Yang, Yong Zhang, Yanfeng Li, Zhenguo Wu and Dahai Zhu*. Myostatin induces cyclin D1 degradation to cause cell cycle arrest through a phosphatidylinositol 3-kinase/AKT/GSK-3 beta pathway and is antagonized by insulin-like growth factor 1. J. Biol. Chem., 2007 Feb 9;282(6):3799-808. Epub 2006 Nov 27.

30. Yong Zhang, Jianwei Ye, Dazhi Chen, Xinyi Zhao, Xingjun Xiao, Sheng Tai, Wei Yang, Dahai Zhu*. Differential Expression Profiling Between the Relative Normal and Dystrophic Muscle Tissues from the Same LGMD Patient. J Transl Med, 2006, 4: 53.

31. Xujun Ma, Qian Qian, Chuanping Yang, Guifeng Liu and Dahai Zhu*. Effect of mouse calcineurin on induction and growth of rice callus transformed by the calcineurin gene. Plant Cell, Tissue and Organ Culture, 2006, 86: 1-6.

32. Wei Yang, Yan Chen, Yong Zhang, Xueyan Wang, Ning Yang, and Dahai Zhu*. Erk1/2 mitogen-activated protein kinase pathway involves in myostatin-regulated differentiation repression. Cancer Res, 2006, 66 (3): 1-7.

33. Xujun Ma, Qian Qian, and Dahai Zhu*. Expression of a calcineurin gene improves salt stress tolerance in transgenic rice. Plant Molecular Biology 2005, 58: 483-495.

34. Wei Yang,Yong Zhang, Guoda Ma, Xinyi Zhao, Yan Chen and Dahai Zhu*. Identification of gene expression modifications in myostatin stimulated myoblasts. Biochem Biophys Res Commun. 2005, 326: 660-666.

35. Zhiliang Gu, Yong Zhang, Peng Shi, Ya-Ping Zhang, Dahai Zhu*, Hui Li. Phylogenetic Analysis of Myostatin Gene in Avian Species. Animal Genetics 2004, 35 (6): 470-472.

36. Zhiliang Gu, Dahai Zhu, Ning Li, Hui Li, Xuemei Deng, Changxin Wu. The Single Nucleotide Polymorphisms of the Chicken Myostatin Gene are Associated with Skeletal Muscle and Adipose Growth. Science in China 2004, 47:26-31.

37. Yanxia Li, Dongcheng Wu, Biao Chen, Alistair Ingram, Lizhi He, Lieqi Liu, Dahai Zhu, Anil Kapoor and Damu Tang. ATM activity contributes to the tumor-suppressing function of p14ARF. Oncogene 2004, 1-11.

38. Haixia Wang, Qiang Zhang, Dahai Zhu*. hSGT Interacts with the N-terminal Region of Myostatin. Biochem Biophys Res Commun. 2003, 311: 877-883.