叶菱秀（Yeap LengSiew）

 抗体多样化研究组

 电话：63846590-776726

 邮箱：yeaplengsiew@shsmu.edu.cn

Mechanisms of Broadly Neutralizing Antibody Generation

The long term goals of the lab are to elucidate mechanism that generates potent neutralizing antibodies and to establish approaches using such antibodies to fight pathogens and diseases. Specifically, we study the mechanisms of Somatic Hypermutation (SHM), a process whereby point mutations and sometimes insertions and deletions (indels) are introduced in the antibody variable region genes for increase binding affinity of the B cells with antigens. SHM is mediated by a DNA mutator, activation induced cytidine deaminase (AID). While the activities of AID at the immunoglobulin (Ig) genes are important for achieving high-affinity neutralizing antibodies, its off-target activities at non-Ig genes could be disastrous (reviewed in Yeap and Meng, Adv Immunol., 2019). For example, AID targeting at oncogenes such as c-myc and Bcl6 may result in translocation and juxtaposition of the Ig enhancer next to the oncogenes, a hallmark in B cell cancer. Thus, the study of the mechanisms of AID targeting is important in understanding immunity and prevention of cancer.

Our lab is particularly interested in studying the mechanisms that generate anti-viral broadly neutralizing antibodies (bnAbs) especially those that are rare and takes a long time to generate such as anti-HIV bnAbs. Such anti-HIV bnAbs have common characteristics such as frequent insertion and deletion in the antibody genes, long CDR3, high frequency of point mutations and are often poly/autoreactive. Our aims are to understand how these special features of the bnAbs are generated during the process of SHM and ultimately apply the knowledge learnt to speed up the process that generate bnAbs. Our long term goal is to establish approaches to efficiently fight diseases and prevent cancer.    

2000-2003 马来西亚沙巴大学 学士

2003-2005 新加坡基因组研究所 研究助理 导师: Bing Lim教授

2005-2010 剑桥大学 博士 导师: Azim Surani教授，表观遗传与干细胞

2010-2015 哈佛大学 博士后 导师: Frederick W. Alt教授

2016-至今 上海交通大学医学院上海市免疫学研究所 研究员，课题组长

1）项目类型：科技部国家重点研发计划子课题

起止年月：2020.10-2024.12

2）项目类型：上海交通大学“ 交大之星” 计划医工交叉研究基金

起止年月：2020.02-2021.01

3）项目类型：国家自然科学基金优秀青年基金

起止年月：2018.01-2020.12

4）项目类型：国家自然科学基金国际合作项目

起止年月：2018.01-2020.12

5）项目类型：国家自然科学基金面上项目

起止年月：2017.01-2020.12

1. Ye X.F., Ren W.C., Liu D.B., Li X.B., Li W., Wang X.H., Meng F.L., Yeap L.S.(叶菱秀), Hou Y., Zhu S.D., Casellas, R., Zhang H.L.*, Wu K.*, Pan Hammarström Q. Genome-wide mutational signatures revealed distinct developmental paths for human B cell lymphomas. J Exp Med, 2021, 218(2): e20200573.

2. Tian Y., Lian C.Y., Chen Y.Y., Wei D., Zhang X.X., Ling Y. *, Wang Y. *, Yeap L.S.* (叶菱秀，共同通讯作者). Sensitivity and specificity of SARS-CoV-2 S1 subunit in COVID-19 serology assays. Cell Discov, 2020, 27(6): 75.

3. Liu, X.J., Liu TT, Shang, Y.F., Dai, P.F., Zhang, W.B., Lee, B.J., Huang, M., Yang D.P., Wu Q., Liu L.D., Zheng, X.Q., Zhou B.O., Dong, J.C., Yeap, L.S. (叶菱秀), Hu, J.Z., Xiao,T.F., Zha, S., Casellas, R., Liu, X.S. and Meng, F.L. ERCC6L2 promotes DNA orientation-specific recombination in mammalian cells. Cell Res, 2020, 30(9): 732-744.

4. Yang, D.P., Sun, Y., Chen, J.J., Zhang, Y., Fan, S.S., Huang, M., Xie, X., Cai, Y.N., Shang, Y.F., Gui, T.T., Sun, L.M., Hu, J.Z., Dong, J.C., Yeap, L.S. (叶菱秀), Wang, X.M., Xiao, W., Meng, F.L. REV7 is required for processing AID initiated DNA lesions in activated B cells. Nat Commun, 2020, 11(1): 2812.

5. Yeap, L.S.* (叶菱秀，共同通讯作者) and Meng F.L.*. Cis- and trans-factors affecting AID targeting and mutagenic outcomes in antibody diversification. Advances in Immunology, 2019, 141: 51-103.

6. Liu, L.D., Huang M., Dai P., Liu T., Fan S., Cheng X., Zhao Y., Yeap, L.S (叶菱秀) and Meng F.L. Intrinsic Nucleotide Preference of Diversifying Base Editors Guides Antibody Ex Vivo Affinity Maturation. Cell Report, 2018, 25: 884-892.

7. Hwang, J.K., Wang C., Du Z., Meyers R.M., Kepler T.B., Neuberg D., Kwong P.D., Mascola J.R., Gordon Joyce M., Bonsignori M., Haynes B.F., Yeap L.S.*(叶菱秀，共同通讯作者) and Alt F.W.* . Sequence intrinsic somatic mutation mechanisms contribute to affinity maturation of VRC01-class HIV-1 broadly neutralizing antibodies. PNAS, 2017, 1-6.

8. Campagno, C., Wang Q., Pighi C., Cheong T.C., Meng F.L., Poggio T., Yeap L.S. (叶菱秀), Atabay E., Blasco R.B., Langellotto F., Voena C., Kasar S.N., Brown J.R., Sun J., Wu C.J., Gostissa M., Alt F.W and Chiarle R. Phosphatidylinositol 3-kinase δ blockade increases genomic instability in B cells. Nature, 2017, 542(7642): 489-493.

9. Yeap, L.S.* (叶菱秀，共同第一作者), Hwang J.K.*, Du Z., Meyers R.M., Meng F.L., Jakubauskaite, A., Liu M., Mani V., Neuberg D., Kepler T.B., Wang, J.H. and Alt F.W. Sequence-Intrinsic Mechanisms that Target AID Mutational Outcomes on Antibody Genes. Cell, 2015, 163 (5): 1124-1137. Featured in Preview by Cornelis Murre, Cell, 163(5): 1055-6.

10. Hwang, J.K.*, Alt F.W. and Yeap L.S.* (叶菱秀，共同第一作者). Related Mechanisms of Antibody Somatic Hypermutation and Class Switch Recombination. Microbiology Spectrum, 2015, 3(1): MDNA3-0037-2014.

11. Yeap, L.S. (叶菱秀，第一作者), Hayashi K. and Surani M.A. ERG-associated protein with SET domain (ESET)-Oct4 interaction regulates pluripotency and represses the trophectoderm lineage. Epigenetics and Chromatin, 2009, 2: 12.

12. Chew, J.L, Loh Y.H., Zhang W., Chen X., Tam W.L., Yeap L.S. (叶菱秀), Li P., Ang Y.S., Lim B., Robson P. and Ng H.H. Reciprocal transcription regulation of Pou5f1 and Sox2 via the Oct4/Sox2 complex in embryonic stem cells. Mol. Cell. Biol, 2005, 25, 6031-6046.