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鲍时来


鲍时来,博士,研究员,博士生导师

  1988年获安徽农学院学士学位,1993年获中国科学技术大学硕士学位,1999年获中国科学技术大学博士学位,1999-2005年先后在美国普渡大学作访问学者和德克萨斯大学安德森癌症研究中心从事博士后研究,2003年回到中国科学院遗传研究所工作。实验室研究方向是个体发育和细胞分化的表观遗传机制。



主要研究内容
 
(一) 揭示调控基因转录和个体发育的“组蛋白密码”
        个体发育和细胞分化过程决定于基因的差异表达。基因的表达与否决定于染色质结构。基因转录表达和沉默就是染色质的重塑过程。组蛋白甲基化、乙酰化、磷酸化和DNA甲基化等表观遗传修饰协同作用,调控染色质重塑过程。调控个体发育的基因同时受到多种组蛋白表观遗传修饰调控,那么决定基因转录和个体发育的组蛋白密码(histone code)是什么目前还不够清楚。我们主要利用模式动物小鼠,研究调控肺形态建成和细胞命运决定的“组蛋白密码”组成、分子识别和信号传导机理。
 
 
 
 
(二) 揭示细胞器高尔基体结构和功能在个体发育和疾病发生中的作用
        真核细胞的高尔基体(Golgi Apparatus)是分泌途径最重要的细胞器,其结构和功能影响细胞内蛋白质等物质的翻译后修饰、折叠和运输。但是高尔基体结构功能缺陷对个体发育和疾病发生的作用目前还不清楚。本课题组的研究重点一是揭示蛋白质甲基化修饰对细胞分泌途径细胞器,特别是高尔基体结构和功能的调控作用。我们利用蛋白质组学方法,研究蛋白质甲基转移酶与高尔基体基质蛋白等蛋白质复合体之间的相互作用,以阐明蛋白质甲基化修饰的作用机理。同时,我们通过建立小鼠Knockout模型,阐明高尔基体结构和功能在调控动物个体发育和疾病发生中的作用。
 
(三) 研究淋巴细胞分化和儿童淋巴细胞白血病发生的表观遗传机制
        造血干细胞(HSC)向淋巴细胞分化过程决定于V(D)J重组和基因的准确转录。这些过程受组蛋白修饰等表观遗传因素的调控。淋巴细胞分化过程不正常就会导致许多疾病的发生,严重的会发生白血病。在儿童时期主要发生淋巴细胞白血病。我们主要研究组蛋白精氨酸甲基化修饰在造血干细胞向淋巴细胞分化中的作用机制。我们与北京儿童医院合作,研究蛋白质甲基化修饰与儿童白血病发生之间的对应关系。通过建立小鼠转基因和Knockout模型,揭示组蛋白精氨酸甲基化等表观遗传修饰调控淋巴细胞分化和儿童白血病发生的作用机理。
 
实验室工作人员:
梅  玫,博士,助理研究员    王进城,博士,助理研究员    李秋伶,博士,助理研究员高勤雨,实验员     
 
在读研究生
何化成,黄翔,李慧君,焦杰,郑宇,王景丽,彭树林
 
客座研究生
许丽婷(博士研究生,首都医科大学北京儿童医院)
 
已毕业研究生
张照亮(博士,UC-Davis博士后),李秋伶(博士,UC-Irvine博士后,2012年回北京),郭少师(博士,美国University of Notre Dame博士后),孙晓甜(博士,美国哥伦比亚大学博士后),杜超豪(博士,四川省),邹振华(博士,美国University of Illinois博士后),章涛(硕士,上海),刘潇(博士研究生,首都医科大学北京儿童医院),岳明辉(博士,美国辛辛那提儿童医院博士后),张培准(博士,北京),应正宙(博士,美国MDACC博士后),刘春宜(博士,美国得克萨斯大学奥斯丁博士后),郑道山(博士,美国博士后),庞潜潜(博士,山东省)
 
实验室以前人员
王昕(博士,NIH博士后,UCLA博士后),周忠卫(硕士,德国Leibniz Institute-Jena大学博士研究生),张娅(博士,NIH博士后),刘长国(博士,浙江农林大学副教授),文雅(博士,Baylor Medical school博士后), 张书沛(硕士,美国UC-Davis), 卫沛(学士,上海),张瑞东(博士,北京儿童医院),郜慧芳(硕士,北京儿童医院),贾慧(硕士,成都市人民医院),孙力涛(硕士,中科院生物物理所博士,美国Scripps Institute 博士后),张寒(博士,美国得克萨斯医学院博士后)

近年发表的代表性论文:*为通信作者)

1. Li Q, Zhao Y, Yue M, Xue Y, Bao S*.(2016)The Protein Arginine Methylase 5 (PRMT5/SKB1) Gene Is Required for the Maintenance of Root Stem Cells in Response to DNA Damage. J Genet Genomics 43(4):187-97.

2. Ying Z, Mei M, Zhang P, Liu C, He H, Gao F, Bao S*. (2015) Histone Arginine Methylation by PRMT7 Controls Germinal Center Formation via Regulating Bcl6 Transcription. The Journal of Immunology 195(4):1538-1547.

3. Zhang H, Cheng H, Wang Q, Zeng X, Chen Y, Yan J, Sun Y, Zhao X, Li W, Gao C, Gong W, Li B, Zhang R, Nan L, Wu Y, Bao S*, Han J,* & Zheng H*. (2015) An advanced fragment analysisbased individualized subtype classification of pediatric acute lymphoblastic leukemia. Sci Rep. 5:12435

4.
Wang Y, Zhu T, Li Q, Liu C, Han F, Chen M, Zhang L, Cui X, Qin Y, Bao S*, Gao F*. (2015) Prmt5 is required for germ cell survival during spermatogenesis in mice. Sci Rep. 5:11031

5. Wang Y, Li Q, Liu C, Han F, Chen M, Zhang L, Cui X, Qin Y, Bao S, Gao F (2015) Protein Arginine Methyltransferase 5 (Prmt5) Is Required for Germ Cell Survival During Mouse Embryonic Development. Biol Reprod.114:127308.

6. Li Q, Li Y, Gu B, Fang L, Zhou P, Bao S, Huang L, Dai X. (2015) Akt Phosphorylates Wnt Coactivator and Chromatin Effector Pygo2 at Serine 48 to Antagonize Its Ubiquitin/Proteasome-mediated Degradation. J Biol Chem. 290(35):21553-67.

7. Zhang H, Zhu L, He H, Zhu S, Zhang W, Liu X, Zhao X, Gao C, Mei M, Bao S*, Zheng H*. (2014) NF-kappa B mediated Up-regulation of CCCTC-binding factor in pediatric acute lymphoblastic leukemia. Molecular Cancer 13(5).

8.
Fan H, Zhang Z, Wang N, Cui Y, Sun H, Liu Y, Wu H, Zheng S, Bao S*, Ling H* (2014) SKB1/PRMT5-mediated histone H4R3 dimethylation of Ib subgroup bHLH genes negatively regulates iron homeostasis in arabidopsis thaliana. Plant Journal 77(2):209-221.

9.
Yue M, Li Q, Zhang Y, Zhao Y, Zhang Z, Bao S*. (2013) Histone H4R3 methylation catalyzed by SKB1/PRMT5 is required for maintaining shoot apical meristem . PLoS One 8(12):.

10. Liu X, Zou L, Zhu L, Zhang H, Du C, Li Z, Gao C, Zhao X, Bao S, Zheng H. (2012) miRNA mediated up-regulation of cochaperone p23 acts as an anti-apoptotic factor in childhood acute lymphoblastic leukemia. Leuk Res. 36(9):1098-104.

11. Zou L, Zhang H, Du C, Liu X, Zhu S, Zhang W, Li Z, Gao C, Zhao X, Mei M, Bao S, Zheng H. (2012) Correlation of SRSF1 and PRMT1 expression with clinical status of pediatric acute lymphoblastic leukemia. J Hematol Oncol. 27;5:42.

12. Sun, L., Wang, M., Lv, Z., Yang, N., Liu, Y., Bao, S., Gong, W., and Xu, R. (2011) Structural Insights into Protein Arginine Symmetric Dimethylation by PRMT5. PNAS 108(51): 20538-20543.

13. Zhang, Z., Zhang, S., Zhang, Y., Wang, X., Li, D., Li, Q., Yue, M., Li, Q., Zhang, Y.E., Xu, Y., Xue, Y., Chong, K., and Bao, S*. (2011). Arabidopsis Floral Initiator SKB1 Confers High Salt Tolerance by Regulating Transcription and Pre-mRNA Splicing through Altering Histone H4R3 and Small Nuclear Ribonucleoprotein LSM4 Methylation. Plant Cell 23 (1):396-411.

14. Guo S, and Bao S*. (2010) srGAP2 arginine methylation regulates cell migration and cell spreading through promoting of dimerization. J Biol Chem 285: 35133-41.

15. Jiang Y, Wang X, Bao S, Guo R, Johnson D, Shen X, Li L. (2010) The INO80 chromatin remodeling complex promotes the removal of UV lesions by the nucleotide excision repair pathway. PNAS 107(40):17274-9.

16. Zhou, Z*., Sun, X*., Zou, Z., Sun, L., Zhang, T., Guo, S., Wen, Y., Liu, L., Wang, Y., Qin, J., Li, L., Gong, W., and Bao, S*. (2010) PRMT5 regulates Golgi apparatus structure through methylation of the golgin GM130. Cell Research 20, 1023-33.

17. Ren, J., Wang, Y., Liang, Y., Zhang, Y., Bao, S. and Xu, Z. (2010). Methylation of ribosomal protein s10 by protein arginine methyltransferase 5 regulates ribosome biogenesis. J Biol Chem. 285, 12695-12705.

18. Li, Z, Zhang, W., Wu, M., Zhu, S., Gao, C., Sun, L., Zhang, R., Qiao, N., Xue, H., Hu, Y., Bao, S*, Zheng, H*. and Han, J.D*. (2009) Gene expression-based classification and regulatory networks of pediatric acute lymphoblastic leukemia. Blood, 114, 4486-4493.

19. Liu, R., Strom, A. L., Zhai, J., Gal, J., Bao, S., Gong, W., and Zhu, H. (2009). Enzymatically inactive adenylate kinase 4 interacts with mitochondrial ADP/ATP translocase. Int J Biochem Cell Biol 41, 1371-1380.

20. Sun L, Zhou Z, Xie X, and Bao S*. (2008) Study on biological activity of various truncations of human PRMT5 in E.coli. Progress in Biochemistry and Biophysics 35 (7).

21. Wang, X., Zhang, Y., Ma, Q., Zhang, Z., Xue, Y., Bao, S*., and Chong, K*. (2007). SKB1-mediated symmetric dimethylation of histone H4R3 controls flowering time in Arabidopsis. EMBO J. 26, 1934-1941.

22. Hou, X., Wang, Y., Zhou, Z., Bao, S., Lin, Y., and Gong, W. (2007). Crystal structure of SAM-dependent O-methyltransferase from pathogenic bacterium Leptospira interrogans. J Struct Biol 159, 523-528.

23. Liu, Z., Zhou, Z., Chen, G., and Bao, S*. (2007). A putative transcriptional elongation factor hIws1 is essential for mammalian cell proliferation. Biochem Biophys Res Commun 353, 47-53.

24. Wang, X., Xu, Y., Han, Y., Bao, S., Du, J., Yuan, M., Xu, Z., and Chong, K. (2006). Overexpression of RAN1 in rice and Arabidopsis alters primordial meristem, mitotic progress, and sensitivity to auxin. Plant Physiol 140, 91-101.

25. Wang, X., Zou, L., Lu, T., Bao, S., Hurov, K. E., Hittelman, W. N., Elledge, S. J., and Li, L. (2006). Rad17 phosphorylation is required for claspin recruitment and Chk1 activation in response to replication stress. Mol Cell 23, 331-341.

26. Cheng, Z., Bao, S., Shan, X., Xu, H., and Gong, W. (2006). Human thioesterase superfamily member 2 (hTHEM2) is co-localized with beta-tubulin onto the microtubule. Biochem Biophys Res Commun 350, 850-853.

27. Bao, S., Lu, T., Wang, X., Zheng, H., Wang, L. E., Wei, Q., Hittelman, W. N., and Li, L. (2004). Disruption of the Rad9/Rad1/Hus1 (9-1-1) complex leads to checkpoint signaling and replication defects. Oncogene 23, 5586-5593.

28. Hu, M. C., Lee, D. F., Xia, W., Golfman, L. S., Ou-Yang, F., Yang, J. Y., Zou, Y., Bao, S., Hanada, N., Saso, H., et al. (2004). IkappaB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. Cell 117, 225-237.

29. Bao, S., Qyang, Y., Yang, P., Kim, H., Du, H., Bartholomeusz, G., Henkel, J., Pimental, R., Verde, F., and Marcus, S. (2001). The highly conserved protein methyltransferase, Skb1, is a mediator of hyperosmotic stress response in the fission yeast Schizosaccharomyces pombe. J Biol Chem 276, 14549-14552.

30. Kim, H. W., Yang, P., Qyang, Y., Lai, H., Du, H., Henkel, J. S., Kumar, K., Bao, S., Liu, M., and Marcus, S. (2001). Genetic and molecular characterization of Skb15, a highly conserved inhibitor of the fission yeast PAK, Shk1. Mol Cell 7, 1095-1101.

31. Li, H., Sherman, D. M., Bao, S., and Sherman, L. A. (2001). Pattern of cyanophycin accumulation in nitrogen-fixing and non-nitrogen-fixing cyanobacteria. Arch Microbiol 176, 9-18.