The bacterial defense system has been engineered to be a versatile gene-editing system in mammals. However, the editing outcomes still require strict surveillance to ensure genome integrity during gene editing. We developed several tools to detect genome editing outcomes and also some new editing tools to improve the safety during genome editing. Next, we are planning to develop new genome editing tools based on the mammalian immune system.
Immunogenomics Laboratory
The immune system protects us from infection or diseases by effectively eliminating pathogens. Lymphocyte receptors, including the B cell receptor (secreted as an antibody) and T cell receptor, target B or T lymphocytes to pathogens and initiate the activation of the adaptive immune response. Lymphocyte receptors show high diversity upon generation and high specificity when recognizing antigens and thus become the most diverse system in humans. Immunogenomics refers to a new branch of molecular immunology that employs genomics methods to study the adaptive immune response based on lymphocyte receptors. Our major research interest is to develop and use genomics assays to investigate the mechanism underlying the diversification of lymphocyte receptors and uncover the two main mysteries in molecular immunology that are allelic exclusion and immune selection of lymphocytes. Lymphocytes protect us from disease, but genome instability can also convert normal lymphocytes to lymphomas or leukemia cells. Therefore, we also focus on how to maintain the genome integrity of lymphocytes.
Antibody Diversification
To study the regulatory mechanism of lymphocyte receptor diversity including RAG-mediated V(D)J recombination and AID-mediated class switch recombination and somatic hypermutation
Antibody Evolution
To develop sequencing-based screening systems to identify monoclonal antibodies and design a cell-based system for antibody generation, maturation, and evolution
Genome Integrity
To study how the DNA response and repair system deals with DNA breaks in the context of chromatin control to maintain the genome integrity of lymphocytes
Genome Editing
Safety assessment of current genome editing toolboxes and development of new editing tools based on the mammalian immune system
Genome Editing
Genomic Integrity
Lymphomas and leukemia are the main killer tumors for kids, largely due to the high genome instability of immune cells including lymphocytes. We focus on the generation of DNA damages, especially double-stranded breaks (DSBs), during the maturation of lymphocytes. The escape of DSBs generated during V(D)J recombination, class switch recombination, and somatic hypermutations may lead to severe chromosomal translocations that threaten genome integrity. Besides, DNA damages arising during the physiological activities of chromatin can also lead to tumorigenesis. Therefore, we are focusing on how cells sense and control the generation and repair of DNA damage.
Antibody Diversification
V(D)J recombination generates a highly diverse spectrum of antibody repertoire and class switch recombination plus somatic hypermutation further diversify antibody. We are developing high-throughput sequencing-based repertoire sequencing assays to trace the adaptive immune response to environment or pathogens, mainly focusing on the change of antibody or T cell receptors. These exploring will help us understand more about the development, maturation, and function of lymphocytes and also facilitate the identification of monoclonal antibodies against the antigen of interest.
Great Team
Our laboratory is well-established for self-motivated young scientists. We warmly welcome you to join us and build a positive, innovative, and active young team together. Our lab will make every effort to create opportunities for each participant to develop their talents and realize their aspirations.
Dr. Jiazhi Hu
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Dr. Yang Liu
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DR. Tingting Gan
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Yuefeng Guo
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Rusen Lu
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Yuhong Wang
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Lingyun Kong
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Xuhao Liu
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Zhengrong Zhangding
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Liqiong Ou
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Haoxin Liang
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Ziting Yang
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Xinyi Liu
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Dr. Yang Liu
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DR. Tingting Gan
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Yuefeng Guo
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Rusen Lu
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Yuhong Wang
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Lingyun Kong
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Xuhao Liu
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Zhengrong Zhangding
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Liqiong Ou
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Haoxin Liang
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Ziting Yang
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Xinyi Liu
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Wanlin Chen
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Wanqin Rao
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Jiayi Chen
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YOU
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Selected Publications
Fork coupling directs DNA replication elongation and termination
Yang Liu, Zhengrong Zhangding, Xuhao Liu, Tingting Gan, Chen Ai, Jinchun Wu, Haoxin Liang, Mohan Chen, Yuefeng Guo, Rusen Lu, Yongpeng Jiang, Xiong Ji, Ning Gao, Daochun Kong, Qing Li, Jiazhi HuScience 2024;383(6688):1215-1222. doi:10.1126/science.adj7606
PMID: 38484065
Cohesin maintains replication timing to suppress DNA damage on cancer genes
Wu J, Liu Y, Zhangding Z, Liu X, Ai C, Gan T, Liang H, Guo Y, Chen M, Liu Y, Yin J, Zhang W, Hu JNat Genet. 2023 Aug;55(8):1347-1358. doi: 10.1038/s41588-023-01458-z.
PMID: 37500731
Safeguarding genome integrity during gene-editing therapy in a mouse model of age-related macular degeneration
Yin J, Fang K, Gao Y, Ou L, Yuan S, Xin C, Wu W, Wu WW, Hong J, Yang H, Hu J.Nat Commun. 2022 Dec 22;13(1):7867. doi: 10.1038/s41467-022-35640-4.
PMID: 36550137
Engineering of efficiency-enhanced Cas9 and base editors with improved gene therapy efficacies
Yin S, Zhang M, Liu Y, Sun X, Guan Y, Chen X, Yang L, Huo Y, Yang J, Zhang X, Han H, Zhang J, Xiao MM, Liu M, Hu J, Wang L, Li D.Mol Ther. 2022 Nov 30:S1525-0016(22)00672-4. doi: 10.1016/j.ymthe.2022.11.014.
PMID: 36457249
CRISPR/Cas9-induced structural variations expand in T lymphocytes in vivo.
Wu J, Zou Z, Liu Y, Liu X, Zhangding Z, Xu M, Hu J.Nucleic Acids Res. 2022 Oct 16:gkac887. doi: 10.1093/nar/gkac887.
PMID: 36243978
Comprehensive assessment of miniature CRISPR-Cas12f nucleases for gene disruption
Xin C, Yin J, Yuan S, Ou L, Liu M, Zhang W, Hu J.Nat Commun. 2022 Sep 24;13(1):5623. doi: 10.1038/s41467-022-33346-1.
PMID: 36153319
Long-term correction of haemophilia B through CRISPR/Cas9 induced homology-independent targeted integration
Chen X, Niu X, Liu Y, Zheng R, Yang L, Lu J, Yin S, Wei Y, Pan J, Sayed A, Ma X, Liu M, Jing F, Liu M, Hu J, Wang L, Li D.J Genet Genomics 2022 Jun 9:S1673-8527(22)00159-X. doi: 10.1016/j.jgg.2022.06.001
PMID: 35691554
The origin of unwanted editing byproducts in gene editing
Yin J, Hu J.Acta Biochim Biophys Sin (Shanghai). 2022 May 25;54(6):1-15. doi: 10.3724/abbs.2022056.
PMID: 35643959
C-terminal deletion-induced condensation sequesters AID from IgH targets in immunodeficiency
Xie X, Gan T, Rao B, Zhang W, Panchakshari RA, Yang D, Ji X, Cao Y, Alt FW, Meng FL, Hu J.EMBO J. 2022 Jun 1;41(11):e109324. doi: 10.15252/embj.2021109324
PMID: 35471583
Cas9 exo-endonuclease eliminates chromosomal translocations during genome editing.
Yin J, Lu R, Xin C, Wang Y, Ling X, Li D, Zhang W, Liu M, Xie W, Kong L, Si W, Wei P, Xiao B, Lee HY, Liu T, Hu J.Nat Commun. 2022 Mar 8;13(1):1204. doi: 10.1038/s41467-022-28900-w.
PMID: 35260581
PEM-seq comprehensively quantifies DNA repair outcomes during gene-editing and DSB repair.
Liu Y, Yin J, Gan T, Liu M, Xin C, Zhang W, Hu J.STAR Protoc. 2022 Jan 17;3(1):101088. doi: 10.1016/j.xpro.2021.101088
PMID: 35462794
Transcription shapes DNA replication initiation to preserve genome integrity.
Liu Y, Ai C, Gan T, Wu J, Jiang Y, Liu X, Lu R, Gao N, Li Q, Ji X, Hu J.Genome Biol. 2021 Jun 9;22(1):176. doi: 10.1186/s13059-021-02390-3.
PMID: 34108027
In-depth assessment of the PAM compatibility and editing activities of Cas9 variants.
Zhang W, Yin J, Zhang-Ding Z, Xin C, Liu M, Wang Y, Ai C, Hu J.Nucleic Acids Res. 2021 Sep 7;49(15):8785-8795. doi: 10.1093/nar/gkab507.
PMID: 34133740
Global detection of DNA repair outcomes induced by CRISPR-Cas9.
Liu M, Zhang W, Xin C, Yin J, Shang Y, Ai C, Li J, Meng FL, Hu J.Nucleic Acids Res. 2021 Sep 7;49(15):8732-8742. doi: 10.1093/nar/gkab686.
PMID: 34365511
RAG2 abolishes RAG1 aggregation to facilitate V(D)J recombination.
Gan T, Wang Y, Liu Y, Schatz DG, Hu J.Cell Rep. 2021 Oct 12;37(2):109824. doi: 10.1016/j.celrep.2021.109824.
PMID: 34644584
Optimizing genome editing strategy by primer-extension-mediated sequencing.
Yin J, Liu M, Liu Y, Wu J, Gan T, Zhang W, Li Y, Zhou Y, Hu J.Cell Discov. 2019 Mar 26;5:18. doi: 10.1038/s41421-019-0088-8. eCollection 2019.
PMID: 30937179
CRISPR/Cas9-mediated targeted chromosome elimination.
Zuo E, Huo X, Yao X, Hu X, Sun Y, Yin J, He B, Wang X, Shi L, Ping J, Wei Y, Ying W, Wei W, Liu W, Tang C, Li Y, Hu J, Yang H.Genome Biol. 2017 Nov 24;18(1):224. doi: 10.1186/s13059-017-1354-4.
PMID: 29178945
Highly sensitive and unbiased approach for elucidating antibody repertoires.
Lin SG, Ba Z, Du Z, Zhang Y, Hu J, Alt FW.Proc Natl Acad Sci U S A. 2016 Jul 12;113(28):7846-51. doi: 10.1073/pnas.1608649113.
PMID: 27354528
Detecting DNA double-stranded breaks in mammalian genomes by linear amplification-mediated high-throughput genome-wide translocation sequencing.
Hu J, Meyers RM, Dong J, Panchakshari RA, Alt FW, Frock RL.Nat Protoc. 2016 May;11(5):853-71. doi: 10.1038/nprot.2016.043. Epub 2016 Mar 31.
PMID: 27031497
Chromosomal loop domains direct the recombination of antigen receptor genes.
Hu J, Zhang Y, Zhao L, Frock RL, Du Z, Meyers RM, Meng FL, Schatz DG, Alt FW.Cell. Nov 5;163(4):947-59. doi: 10.1016/j.cell.2015.10.016.
PMID: 26593423
Genome-wide detection of DNA double-stranded breaks induced by engineered nucleases.
Frock RL, Hu J, Meyers RM, Ho YJ, Kii E, Alt FW.Nat Biotechnol. 2015 Feb;33(2):179-86. doi: 10.1038/nbt.3101.
PMID: 25503383
Developmental propagation of V(D)J recombination-associated DNA breaks and translocations in mature B cells via dicentric chromosomes.
Hu J, Tepsuporn S, Meyers RM, Gostissa M, Alt FW.Proc Natl Acad Sci U S A. 2014 Jul 15;111(28):10269-74. doi: 10.1073/pnas.1410112111.
PMID: 24982162
Mechanisms that can promote peripheral B-cell lymphoma in ATM-deficient mice.
Tepsuporn S, Hu J, Gostissa M, Alt FW.Cancer Immunol Res. 2014 Sep;2(9):857-66. doi: 10.1158/2326-6066.CIR-14-0090.
PMID: 24913718
The intra-S phase checkpoint targets Dna2 to prevent stalled replication forks from reversing.
Hu J, Sun L, Shen F, Chen Y, Hua Y, Liu Y, Zhang M, Hu Y, Wang Q, Xu W, Sun F, Ji J, Murray JM, Carr AM, Kong D.Cell. 2012 Jun 8;149(6):1221-32. doi: 10.1016/j.cell.2012.04.030.
PMID: 22682245