Yuan Zhuang

Overview:

Research in our laboratory focuses on molecular mechanism of lymphocyte development and genetic basis of lymphoid diseases such as leukemia and autoimmune disorders. We are using mouse models to investigate the role of E2A and other related transcription factors in lymphocyte development and immune function. We have shown that E2A plays an essential role in regulating both B and T cell development. Mice deficient for E2A cannot produce any B cell and exhibit high incidence of T cell leukemia. Separate studies also indicated that E2A is involved in the development of autoimmune disorders. Our current and future studies are to combine genetic, molecular biology, and immunology means to determine gene expression programs during lymphocyte development.

The mechanistic studies of gene function in animal models provide important clues in understanding relevant human diseases. It has been shown that about 20-30% of pediatric acute lymphocytic leukemias (ALL) are linked to chromosomal rearrangements at the E2A gene locus. Most of these genetic defects produce oncogenic forms of E2A proteins, which are the possible cause of leukemia. The use of animal models allows us to further define the molecular events underlying the disease development. Our long term goal is to provide molecular basis for early diagnosis and treatment of relevant lymphoid system diseases. 

Laboratory website:  Http://sites.duke.edu/zhuanglab

Positions:

Professor of Immunology

Immunology
School of Medicine

Professor of Molecular Genetics and Microbiology

Molecular Genetics and Microbiology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 1989

Yale University

Grants:

Organization and Function of Cellular Structure

Administered By
Basic Science Departments
Awarded By
National Institutes of Health
Role
Mentor
Start Date
End Date

Basic Immunology Training Program

Administered By
Immunology
Awarded By
National Institutes of Health
Role
Mentor
Start Date
End Date

Cancer Center Core Support Grant

Administered By
Medicine, Medical Oncology
Awarded By
National Institutes of Health
Role
Co-Principal Investigator
Start Date
End Date

Comprehensive Cancer Center Core Support Grant

Administered By
Medicine, Medical Oncology
Awarded By
National Institutes of Health
Role
Co-Principal Investigator
Start Date
End Date

Training Program in Inflammatory and Immunological Diseases

Administered By
Medicine, Rheumatology and Immunology
Awarded By
National Institutes of Health
Role
Preceptor
Start Date
End Date

Publications:

Conversion of effector CD4+ T cells to a CD8+ MHC II-recognizing lineage.

CD4+ and CD8+ T cells are dichotomous lineages in adaptive immunity. While conventionally viewed as distinct fates that are fixed after thymic development, accumulating evidence indicates that these two populations can exhibit significant lineage plasticity, particularly upon TCR-mediated activation. We define a novel CD4-CD8αβ+ MHC II-recognizing population generated by lineage conversion from effector CD4+ T cells. CD4-CD8αβ+ effector T cells downregulated the expression of T helper cell-associated costimulatory molecules and increased the expression of cytotoxic T lymphocyte-associated cytotoxic molecules. This shift in functional potential corresponded with a CD8+-lineage skewed transcriptional profile. TCRβ repertoire sequencing and in vivo genetic lineage tracing in acutely infected wild-type mice demonstrated that CD4-CD8αβ+ effector T cells arise from fundamental lineage reprogramming of bona fide effector CD4+ T cells. Impairing autophagy via functional deletion of the initiating kinase Vps34 or the downstream enzyme Atg7 enhanced the generation of this cell population. These findings suggest that effector CD4+ T cells can exhibit a previously unreported degree of skewing towards the CD8+ T cell lineage, which may point towards a novel direction for HIV vaccine design.
Authors
Robins, E; Zheng, M; Ni, Q; Liu, S; Liang, C; Zhang, B; Guo, J; Zhuang, Y; He, Y-W; Zhu, P; Wan, Y; Li, Q-J
MLA Citation
Robins, Elizabeth, et al. “Conversion of effector CD4+ T cells to a CD8+ MHC II-recognizing lineage.Cell Mol Immunol, Feb. 2020. Pubmed, doi:10.1038/s41423-019-0347-5.
URI
https://scholars.duke.edu/individual/pub1433220
PMID
32066854
Source
pubmed
Published In
Cell Mol Immunol
Published Date
DOI
10.1038/s41423-019-0347-5

TCR Repertoires of Thymic Conventional and Regulatory T Cells: Identification and Characterization of Both Unique and Shared TCR Sequences.

Thymic regulatory T cells (tTreg) are critical in the maintenance of normal T cell immunity and tolerance. The role of TCR in tTreg selection remains incompletely understood. In this study, we assessed TCRα and TCRβ sequences of mouse tTreg and thymic conventional CD4+ T cells (Tconv) by high-throughput sequencing. We identified αβ TCR sequences that were unique to either tTreg or Tconv and found that these were distinct as recognized by machine learning algorithm and by preferentially used amino acid trimers in αβ CDR3 of tTreg. In addition, a proportion of αβ TCR sequences expressed by tTreg were also found in Tconv, and machine learning classified the great majority of these shared αβ TCR sequences as characteristic of Tconv and not tTreg. These findings identify two populations of tTreg, one in which the regulatory T cell fate is associated with unique properties of the TCR and another with TCR properties characteristic of Tconv for which tTreg fate is determined by factors beyond TCR sequence.
Authors
Ko, A; Watanabe, M; Nguyen, T; Shi, A; Achour, A; Zhang, B; Sun, X; Wang, Q; Zhuang, Y; Weng, N-P; Hodes, RJ
MLA Citation
Ko, Annette, et al. “TCR Repertoires of Thymic Conventional and Regulatory T Cells: Identification and Characterization of Both Unique and Shared TCR Sequences.J Immunol, vol. 204, no. 4, Feb. 2020, pp. 858–67. Pubmed, doi:10.4049/jimmunol.1901006.
URI
https://scholars.duke.edu/individual/pub1427342
PMID
31924652
Source
pubmed
Published In
J Immunol
Volume
204
Published Date
Start Page
858
End Page
867
DOI
10.4049/jimmunol.1901006

Putative biomarkers for predicting tumor sample purity based on gene expression data.

BACKGROUND: Tumor purity is the percent of cancer cells present in a sample of tumor tissue. The non-cancerous cells (immune cells, fibroblasts, etc.) have an important role in tumor biology. The ability to determine tumor purity is important to understand the roles of cancerous and non-cancerous cells in a tumor. METHODS: We applied a supervised machine learning method, XGBoost, to data from 33 TCGA tumor types to predict tumor purity using RNA-seq gene expression data. RESULTS: Across the 33 tumor types, the median correlation between observed and predicted tumor-purity ranged from 0.75 to 0.87 with small root mean square errors, suggesting that tumor purity can be accurately predicted υσινγ expression data. We further confirmed that expression levels of a ten-gene set (CSF2RB, RHOH, C1S, CCDC69, CCL22, CYTIP, POU2AF1, FGR, CCL21, and IL7R) were predictive of tumor purity regardless of tumor type. We tested whether our set of ten genes could accurately predict tumor purity of a TCGA-independent data set. We showed that expression levels from our set of ten genes were highly correlated (ρ = 0.88) with the actual observed tumor purity. CONCLUSIONS: Our analyses suggested that the ten-gene set may serve as a biomarker for tumor purity prediction using gene expression data.
Authors
Li, Y; Umbach, DM; Bingham, A; Li, Q-J; Zhuang, Y; Li, L
MLA Citation
Li, Yuanyuan, et al. “Putative biomarkers for predicting tumor sample purity based on gene expression data.Bmc Genomics, vol. 20, no. 1, Dec. 2019, p. 1021. Pubmed, doi:10.1186/s12864-019-6412-8.
URI
https://scholars.duke.edu/individual/pub1425859
PMID
31881847
Source
pubmed
Published In
Bmc Genomics
Volume
20
Published Date
Start Page
1021
DOI
10.1186/s12864-019-6412-8

Differential functions for the transcription factor E2A in positive and negative gene regulation in pre-B lymphocytes. (vol 279, pg 45028, 2004)

Authors
Greenbaum, S; Lazorchak, AS; Zhuang, Y
MLA Citation
Greenbaum, S., et al. “Differential functions for the transcription factor E2A in positive and negative gene regulation in pre-B lymphocytes. (vol 279, pg 45028, 2004).” Journal of Biological Chemistry, vol. 280, no. 16, AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, Apr. 2005, pp. 16528–16528.
URI
https://scholars.duke.edu/individual/pub1441902
Source
wos
Published In
The Journal of Biological Chemistry
Volume
280
Published Date
Start Page
16528
End Page
16528

The whole-genome landscape of Burkitt lymphoma subtypes.

Burkitt lymphoma (BL) is an aggressive, MYC-driven lymphoma comprising 3 distinct clinical subtypes: sporadic BLs that occur worldwide, endemic BLs that occur predominantly in sub-Saharan Africa, and immunodeficiency-associated BLs that occur primarily in the setting of HIV. In this study, we comprehensively delineated the genomic basis of BL through whole-genome sequencing (WGS) of 101 tumors representing all 3 subtypes of BL to identify 72 driver genes. These data were additionally informed by CRISPR screens in BL cell lines to functionally annotate the role of oncogenic drivers. Nearly every driver gene was found to have both coding and non-coding mutations, highlighting the importance of WGS for identifying driver events. Our data implicate coding and non-coding mutations in IGLL5, BACH2, SIN3A, and DNMT1. Epstein-Barr virus (EBV) infection was associated with higher mutation load, with type 1 EBV showing a higher mutational burden than type 2 EBV. Although sporadic and immunodeficiency-associated BLs had similar genetic profiles, endemic BLs manifested more frequent mutations in BCL7A and BCL6 and fewer genetic alterations in DNMT1, SNTB2, and CTCF. Silencing mutations in ID3 were a common feature of all 3 subtypes of BL. In vitro, mass spectrometry-based proteomics demonstrated that the ID3 protein binds primarily to TCF3 and TCF4. In vivo knockout of ID3 potentiated the effects of MYC, leading to rapid tumorigenesis and tumor phenotypes consistent with those observed in the human disease.
Authors
Panea, RI; Love, CL; Shingleton, JR; Reddy, A; Bailey, JA; Moormann, AM; Otieno, JA; Ong'echa, JM; Oduor, CI; Schroeder, KMS; Masalu, N; Chao, NJ; Agajanian, M; Major, MB; Fedoriw, Y; Richards, KL; Rymkiewicz, G; Miles, RR; Alobeid, B; Bhagat, G; Flowers, CR; Ondrejka, SL; Hsi, ED; Choi, WWL; Au-Yeung, RKH; Hartmann, W; Lenz, G; Meyerson, H; Lin, Y-Y; Zhuang, Y; Luftig, MA; Waldrop, A; Dave, T; Thakkar, D; Sahay, H; Li, G; Palus, BC; Seshadri, V; Kim, SY; Gascoyne, RD; Levy, S; Mukhopadyay, M; Dunson, DB; Dave, SS
MLA Citation
Panea, Razvan I., et al. “The whole-genome landscape of Burkitt lymphoma subtypes.Blood, vol. 134, no. 19, Nov. 2019, pp. 1598–607. Pubmed, doi:10.1182/blood.2019001880.
URI
https://scholars.duke.edu/individual/pub1415067
PMID
31558468
Source
pubmed
Published In
Blood
Volume
134
Published Date
Start Page
1598
End Page
1607
DOI
10.1182/blood.2019001880