Mechanisms of Broadly Neutralizing Antibody Generation

The long term goals of the lab are to elucidate mechanism that generate 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.

1.  Huang M.E., Qin Y.N., Shang Y.F., Hao Q., Zhan C.Z., Lian C.Y., Luo S.M., Liu L.D., Zhang S.X., Zhang Y., Wo Y., Li N., Wu S.H., Gui T.T., Wang B.B., Luo Y.F., Cai Y.N., Liu X.J.,Xu Z.Y., Dai P.F., Li S.M., Zhang L., Dong J.C., Wang J., Zheng X.Q., Xu Y.J., Sun Y.H., Wu W., Yeap L.S. *（叶菱秀，共同通讯作者）, Meng F.L.*.C-to-G editing generates double-strand breaks causing deletion, transversion and translocation, Nat Cell Biol, 2024, 26(2):294-304.  [Link]

2.  Wang Y.Y.,  Meng F.L.*，Yeap L.S. *（叶菱秀，最后通讯作者）. DNA flexibility can shape the preferential hypermutation of antibody genes, Trends Immunol,2024, S1471-4906(24)00005-X. [Link]

3.  Wang Y.Y., Zhang S.X., Zheng X.Q., Yeap L.S. *（叶菱秀，共同通讯作者）, Meng F.L.*. A high-throughput protocol for deamination of long single-stranded DNA and oligo pools containing complex sequences, STAR Protoc, 2023, 4(4):102602. Online ahead of print. [Link]

4.  Wang Y.Y., Zhang S.X., Yang X.R., Hwang J.K., Zhan C.Z., Lian C.Y., Wang C., Gui T.T., Wang B.B., Xie X., Dai P.F., Zhang L., Tian Y., Zhang H.Z., Han C., Cai Y.N., Hao H., Ye X.F., Liu X.J., Liu J.Q., Cao Z.W., Huang S.H., Song J., Pan-Hammarström Q., Zhao Y.F., Alt F.W., Zheng X.Q., Da L.T., Yeap L.S. *（叶菱秀，共同通讯作者）, Meng F.L^*. Mesoscale dna feature in antibody-coding sequence facilitates somatic hypermutation, Cell, 2023, 186(10): 2193-2207.e19.  [Link]

5.  Hao Q., Zhan C.Z.,  Lian C.Y., Luo S.M., Cao W.Y., Wang B.B, Xie X., Ye X.F., Gui T.T.,  Voena C., Pighi C., Wang Y.Y., Tian Y., Wang X., Dai P.F., Cai Y.N., Liu  X.J., Ouyang S.Q., Sun S.Q., Hu Q.W., Liu J., Ye Y.Q., Zhao J.K., Lu  A., Wang J.Y., Huang C.X., Su B., Meng F.L., Chiarle R.*, Pan-Hammarström Q.*, Yeap L.S.* （叶菱秀，最后通讯作者）. DNA  repair mechanisms that promote insertion-deletion events during  immunoglobulin gene diversification, Sci Immunol, 2023,  8(81): eade1167.  [Link]

6.  Gao B., He L.H., Bao Y.J., Chen Y.Y., Lu G.Z., Zhang Y., Xu Y.J., Su B., Xu J.*, Wang Y. *, Yeap L.S.* （叶菱秀，最后通讯作者）. Repeated Vaccination of Inactivated SARS-CoV-2 Vaccine Dampens Neutralizing Antibodies Against Omicron Variants in Breakthrough Infection.Cell Res, 2023, 33(3): 258-261.  [Link]  

7.  Lin K., Zhou Y.W., Ai J.W., Wang Y.A., Zhang S.X., Qiu C., Lian C.Y., Gao B., Liu T.T., Wang H.Y., Zhang H.C., Zhang Y., Fu Z.F., Li D., Jiang N., Guo J.X., Wu J., Wang Y.O., Song S.S., Li Q., Yin Y.A., Xia J., Xu Y.J., Yeap L.S.（叶菱秀）, Zheng X.Q., Gu Y., Liu H.Y.*, Zhang W.H.*,  Meng F.L.*. B cell receptor signatures associated with strong and poor SARS-CoV-2 vaccine responses. Emerg Microbes Infect, 2022, 11 (1): 452-464.   [Link]  

8.  Feng A.Q, Hao Q* and Yeap L.S.* （叶菱秀，最后通讯作者）. Contribution of rare mutational outcomes to broadly neutralizing antibodies. Acta Biochim Biophys Sin (Shanghai), 2022, 54(6): 820-827.  [Link]  

9.  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.  [Link]

10.  Liu L.D., Lian C.Y., Yeap, L.S.*（叶菱秀，共同通讯作者） and Meng F.L.*. The development of neutralizing antibodies against SARS-CoV-2 and their common features. J Mol Cell Biol, 2020, 12(12):  980-986.  [Link]

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

12.  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.  [Link] 

13.  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. and Meng F.L.*. REV7 is required for processing AID initiated DNA lesions in activated B cells. Nat Commun, 2020, 11(1): 2812.  [Link]

14.  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. Adv Immunol, 2019, 141: 51-103.  [Link]

15.  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.  [Link]

16.  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.  [Link]

17.  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.  [Link]

18.  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): 1124-37. *co-first authors. Featured in Preview by Cornelis Murre, Cell 163(5):1055-1056.  [Link]

19.  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. Microbiol Spectr, 2015, 3(1):MDNA3-0037-2014. doi:10.1128/microbiolspec.MDNA3-0037-2014.  [Link]

20.  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 Chromatin, 2009, 2:12.  [Link]

21.  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.  [Link]