研究生教育

沈立，浙江大学生命科学研究院教授、研究员、博士生导师

研究与成果：

一）DNA甲基化和去甲基化的动态调控及其与其它表观遗传调控机制（如组蛋白修饰和非编码RNA）间的相互作用；

二）表观遗传对发育和细胞全能性的调控机制，以及在多能性干细胞诱导和细胞转分化中的调控作用；

三）表观遗传调控网络在肿瘤和免疫系统疾病的发生、发展中的调控机制，以及以表观遗传调控蛋白为靶点的新药研究；

四）高通量测序技术和微流控芯片在表观遗传学研究中的新应用，以及相关数据分析软件的开发。

代表性论文：

[1] Zhang, Q., Xiao, M., Gu, S., Xu, Y., Liu, T., Li, H., Yu, Y., Qin, L., Zhu, Y., Chen, F., Wang, Y., Ding, C., Wu, H., Ji, H., Chen, Z., Zu, Y., Malkoski, S., Li, Y., Liang, T., Ji, J., Qin, J., Xu, P., Zhao, B., Shen, L., Lin, X. & Feng, X.H. (2019).  ALK Phosphorylates SMAD4 On Tyrosine to Disable TGF-beta Tumour Suppressor Functions. Nat Cell Biol, 21, 179-189

[2] Matoba, S., Wang, H., Jiang, L., Lu, F., Iwabuchi, K. A., Wu, X., Inoue, K., Yang, L., Press, W., Lee, J. T., Ogura, A., Shen, L.#, and Zhang, Y#. (2018). Loss of H3K27me3 Imprinting in Somatic Cell Nuclear Transfer Embryos Disrupts Post-Implantation Development. Cell Stem Cell, 23(3): 343-354

[3] Zhang, J., Zhang, Y. L., Zhao, L. W., Guo, J. X., Yu, J. L., Ji, S. Y., Cao, L. R., Zhang, S. Y., Shen, L., Ou, X. H., and Fan, H. Y. (2018). Mammalian nucleolar protein DCAF13 is essential for ovarian follicle maintenance and oocyte growth by mediating rRNA processing. Cell Death Differ.

[4] Sha, Q. Q., Yu, J. L., Guo, J. X., Dai, X. X., Jiang, J. C., Zhang, Y. L., Yu, C., Ji, S. Y., Jiang, Y., Zhang, S. Y., Shen, L., Ou, X. H., and Fan, H. Y. (2018). CNOT6L couples the selective degradation of maternal transcripts to meiotic cell  cycle progression in mouse oocyte. EMBO J,e

[5] Diao, D., Wang, H., Li, T., Shi, Z., Jin, X., Sperka, T., Zhu, X., Zhang, M., Yang, F., Cong, Y., Shen, L., Zhan, Q., Yan, J., Song, Z., and Ju, Z. (2018). Telomeric epigenetic response mediated by Gadd45a regulates stem cell aging and lifespan. EMBO Rep, 19(10)e45494.

[6] Guo, A., Huang, S., Yu, J., Wang, H., Li, H., Pei, G.#, and Shen, L.# (2017). Single-cell Dynamic Analysis of Mitosis in Haploid Embryonic Stem Cells Shows the Prolonged Metaphase and its Association with Self-diploidization. Stem Cell Reports. 8, 1124–1134. 

[7] Li, H., Guo, A., Xie, Z., Tu, W., Yu, J., Wang, H., Zhao, J., Zhong, C., Kang, J., Li, J., Huang, S.#, and Shen, L.# (2017). Stabilization of mouse haploid embryonic stem cells with combined kinase and signal modulation. Scientific Reports. 7, 13222.

[8]  Gao, L., Guan, W., Wang, M., Wang, H., Yu, J., Liu, Q., Qiu, B., Yu, Y., Ping, Y., Bian, X., Shen, L.#, and Pei, G.# (2017). Direct Generation of Human Neuronal Cells from Adult Astrocytes by Small Molecules. Stem Cell Reports. 8, 538–547.

[9] Shi, M. and Shen, L. (2017). The Molecular Basis of DNA Demethylation. Chapter 3 of the book “DNA and Histone Methylation as Cancer Targets” (Springer Nature).

[10]  Lee, C.-C. *, Peng, S.-H. *, Shen, L. *, Lee, C.-F., Du, T.-H., Kang, M.-L., Xu, G.-L., Upadhyay, A.K., Cheng, X., Yan, Y.-T., et al. (2017). The Role of N-α-acetyltransferase 10 Protein in DNA Methylation and Genomic Imprinting. Molecular Cell. 68, 89–103.

[11] Yu C, Fan X, Sha Q Q, Wang H H, Li B T, Dai X X, Shen L, Liu J, Wang L, Liu K, Tang F, Fan H Y. (2017). CFP1 Regulates Histone H3K4 Trimethylation and Developmental Potential in Mouse Oocytes. Cell Rep, 20(5): 1161-1172.

[12] Liu S, Chen S, Li X, Wu S, Zhang Q, Jin Q, Hu L, Zhou R, Yu Z, Meng F, Wang S, Huang Y, Ye S, Shen L, Xia Z, Zou J, Feng X H, Xu P. (2017). Lck/Hck/Fgr-Mediated Tyrosine Phosphorylation Negatively Regulates TBK1 to Restrain Innate Antiviral Responses. Cell Host Microbe. 21(6): 754-768.

[13] Guo, G., Pinello, L., Han, X., Lai, S., Shen, L., Lin, T. W., Zou, K., Yuan, G. C., and Orkin, S. H. (2016). Serum-Based Culture Conditions Provoke Gene Expression Variability in Mouse Embryonic Stem Cells as Revealed by Single-Cell Analysis. Cell Rep.14,956-965

[14]  Inoue, A., Shen, L., Matoba, S., & Zhang, Y. (2015). Haploinsufficiency, but not defective paternal 5mC oxidation, accounts for the developmental defects of maternal Tet3 knockouts. Cell Rep.10: 463-470.

[15] Matoba, S., Liu, Y., Lu, F., Iwabuchi, K.A., Shen, L., Inoue, A., and Zhang, Y. (2014). Embryonic Development following Somatic Cell Nuclear Transfer Impeded by Persisting Histone Methylation. Cell. 159, 884–895.

[16] Wu, H., Wu, X., Shen, L., and Zhang, Y. (2014). Single-base resolution analysis of active DNA demethylation using methylase-assisted bisulfite sequencing. Nat Biotechnol. 32, 1231–1240.

[17] Shen, L.*, Inoue, A.*, He, J., Liu, Y., Lu, F., and Zhang Y. (2014). Tet3 and DNA Replication Mediate Demethylation of Both the Maternal and Paternal Genomes in Mouse Zygotes. Cell Stem Cell. 15, 459–470.

[18] Shen, L.*, Song, C.X.*, He, C., Zhang, Y. (2014). Mechanism and Function of Oxidative Reversal of DNA and RNA Methylation. Annu Rev Biochem. 83, 585-614.

[19] Yamaguchi, S., Shen, L., Liu, Y., Sendler, D., and Zhang, Y. (2013). Role of Tet1 in genomic imprinting erasure. Nature. 504, 460-464.

[20] Lin, F., Shen, L., Jang, C., Falnes, P., and Zhang, Y. (2013) Ikbkap/Elp1 deficiency causes male infertility by disrupting meiotic progression. PLoS Genet. 9, e1003516. 

[21] Shen, L.*, Wu, H.*, Diep, D., Yamaguchi, S., D'Alessio, A., Fung, H., Zhang, K., and Zhang, Y. (2013). Genome-wide analysis reveals TET- and TDG-dependent 5-methylcytosine oxidation dynamics. Cell. 153, 692-706

[22] Shen, L., Zhang, Y. (2013). 5-Hydroxymethylcytosine: generation, fate, and genomic distribution. Current Opinion in Cell Biology. 25, 289–296.

[23] He, J., Shen, L., Wan, M., Taranova, O., Wu, H., and Zhang, Y. (2013). Kdm2b maintains murine embryonic stem cell status by recruiting PRC1 complex to CpG islands of developmental genes. Nat Cell Biol. 15, 373–384.

[24] Yamaguchi, S., Hong, K., Liu, R., Inoue, A., Shen, L., Zhang, K., and Zhang, Y. (2013). Dynamics of 5-methylcytosine and 5-hydroxymethylcytosine during germ cell reprogramming. Cell Res. 23, 329-339.

[25] Yamaguchi, S.*, Hong, K.*, Liu, R.*, Shen, L., Inoue, A., Deip, D., Zhang, K., and Zhang, Y. (2012). Tet1 controls meiosis by regulating meiotic gene expression. Nature. 492, 443–447.  

[26] Nabel, C., Jia, H., Ye, Y., Shen, L., Goldschmidt, H., Stivers, J., Zhang, Y., Kohli, R. (2012) AID/APOBEC deaminases disfavor modified cytosines implicated in DNA demethylation. Nat ChemBiol. 14(5):457-66.

[27] Shen, L., Zhang, Y. (2012) Enzymatic Analysis of the Tet proteins. Methods Enzymol. 512, 93-105.

[28] Inoue, A., Shen, L., Dai, Q., He, C., and Zhang, Y. (2011). Generation and replication-dependent dilution of 5fC and 5caC during mouse preimplantation development. Cell Res. 21, 1670-1676.

[29] Ito, S.*, Shen, L.*, Dai, Q., Wu, S.C., Collins, L.B., Swenberg, J.A., He, C., and Zhang, Y. (2011). Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science. 333, 1300-1303.

[30] Chen, T.*, Shen, L.*, Yu, J.*, Wan, H.*, Guo, A., Chen, J., Long, Y., Zhao, J., and Pei, G. (2011). Rapamycin and other longevity-promoting compounds enhance the generation of mouse induced pluripotent stem cells. Aging Cell.10, 908-911.

[31] Shen, L., Gao, G., Zhang, Y., Zhang, H., Ye, Z., Huang, S., Huang, J., and Kang, J. (2010). A single amino acid substitution confers enhanced methylation activity of mammalian Dnmt3b on chromatin DNA. Nucleic Acids Res. 38, 6054-6064.

[32] Zou, L.*, Wang, Z.*, Shen, L., Bao, G.B., Wang, T., Kang, J.H., and Pei, G. (2007). Receptor tyrosine kinases positively regulate BACE activity and Amyloid-beta production through enhancing BACE internalization. Cell Res. 17, 389-401. 

[33] Yu, Y.X., Shen, L., Xia, P., Tang, Y.W., Bao, L., and Pei, G. (2006). Syntaxin 1A promotes the endocytic sorting of EAAC1 leading to inhibition of glutamate transport. J Cell Sci. 119, 3776-3787.

[34] Xu, N.J.*, Yu, Y.X.*, Zhu, J.M., Liu, H., Shen, L., Zeng, R., Zhang, X., and Pei, G. (2004). Inhibition of SNAP-25 phosphorylation at Ser187 is involved in chronic morphine-induced down-regulation of SNARE complex formation. J BiolChem. 279, 40601-40608.

招生信息：表观遗传学方向硕士、博士