Bio

Professional Education


  • Doctor of Philosophy, Zhejiang University (2016)

Stanford Advisors


Publications

All Publications


  • The DNA Repair Nuclease MRE11A Functions as a Mitochondrial Protector and Prevents T Cell Pyroptosis and Tissue Inflammation. Cell metabolism Li, Y., Shen, Y., Jin, K., Wen, Z., Cao, W., Wu, B., Wen, R., Tian, L., Berry, G. J., Goronzy, J. J., Weyand, C. M. 2019

    Abstract

    In the autoimmune disease rheumatoid arthritis (RA), CD4+ Tcells promote pro-inflammatory effector functions by shunting glucose away from glycolysis and ATP production. Underlying mechanisms remain unknown, and here we implicate the DNA repair nuclease MRE11A in the cells' bioenergetic failure. MRE11A deficiency in RA Tcells disrupted mitochondrial oxygen consumption and suppressed ATP generation. Also, MRE11A loss of function caused leakage of mitochondrial DNA (mtDNA) into the cytosol, triggering inflammasome assembly, caspase-1 activation, and pyroptotic cell death. Caspase-1 activation was frequent in lymph-node-residing Tcells in RA patients. Invivo, pharmacologic and genetic inhibition of MRE11A resulted in tissuedeposition of mtDNA, caspase-1 proteolysis, andaggressive tissue inflammation. Conversely, MRE11A overexpression restored mitochondrial fitness and shielded tissue from inflammatory attack. Thus, the nuclease MRE11A regulates a mitochondrial protection program, and MRE11A deficiency leads to DNA repair defects, energy production, and failure and loss of tissue homeostasis.

    View details for DOI 10.1016/j.cmet.2019.06.016

    View details for PubMedID 31327667

  • CXXC finger protein 1 is critical for T-cell intrathymic development through regulating H3K4 trimethylation NATURE COMMUNICATIONS Cao, W., Guo, J., Wen, X., Miao, L., Lin, F., Xu, G., Ma, R., Yin, S., Hui, Z., Chen, T., Guo, S., Chen, W., Huang, Y., Liu, Y., Wang, J., Wei, L., Wang, L. 2016; 7: 11687

    Abstract

    T-cell development in the thymus is largely controlled by an epigenetic program, involving in both DNA methylation and histone modifications. Previous studies have identified Cxxc1 as a regulator of both cytosine methylation and histone 3 lysine 4 trimethylation (H3K4me3). However, it is unknown whether Cxxc1 plays a role in thymocyte development. Here we show that T-cell development in the thymus is severely impaired in Cxxc1-deficient mice. Furthermore, we identify genome-wide Cxxc1-binding sites and H3K4me3 modification sites in wild-type and Cxxc1-deficient thymocytes. Our results demonstrate that Cxxc1 directly controls the expression of key genes important for thymocyte survival such as RORγt and for T-cell receptor signalling including Zap70 and CD8, through maintaining the appropriate H3K4me3 on their promoters. Importantly, we show that RORγt, a direct target of Cxxc1, can rescue the survival defects in Cxxc1-deficient thymocytes. Our data strongly support a critical role of Cxxc1 in thymocyte development.

    View details for DOI 10.1038/ncomms11687

    View details for Web of Science ID 000376205000001

    View details for PubMedID 27210293

    View details for PubMedCentralID PMC4879243

  • Runt-related transcription factor 3 is involved in the altered phenotype and function in ThPok-deficient invariant natural killer T cells CELLULAR & MOLECULAR IMMUNOLOGY Liu, X., Yin, S., Cao, W., Fan, W., Yu, L., Yin, L., Wang, L., Wang, J. 2014; 11 (3): 232–44

    Abstract

    The interplay between the CD4-lineage transcription factor ThPok and the CD8-lineage transcription factor, runt-related transcription factor 3 (Runx3), in T-cell development has been extensively documented. However, little is known about the roles of these transcription factors in invariant natural killer T (iNKT) cell development. CD1d-restricted iNKT cells are committed to the CD4(+)CD8(-) and CD4(-)CD8(-) sublineages, which respond to antigen stimulation with rapid and potent release of T helper (Th) 1 and Th2 cytokines. However, previous reports have demonstrated a new population of CD8(+) NKT cells in ThPok-deficient mice. In the current study, we sought to determine whether Runx3 was involved in the re-expression of CD8 and function of iNKT cells in the absence of ThPok. We used mice lacking Runx3, ThPok or both and verified that Runx3 was partially responsible for the appearance of CD8(+) iNKT cells in ThPok knockout mice. Additionally, Runx3 participated in the immune response mediated by iNKT cells in a model of α-galactosylceramide-induced acute hepatitis. These results indicate that Runx3 is crucial for the phenotypic and functional changes observed in ThPok-deficient iNKT cells.

    View details for DOI 10.1038/cmi.2014.3

    View details for Web of Science ID 000335374000005

    View details for PubMedID 24561456

    View details for PubMedCentralID PMC4085493

  • Klf10 inhibits IL-12p40 production in macrophage colony-stimulating factor-induced mouse bone marrow-derived macrophages EUROPEAN JOURNAL OF IMMUNOLOGY Zhang, W., Wang, X., Xia, X., Liu, X., Suo, S., Guo, J., Li, M., Cao, W., Cai, Z., Hui, Z., Subramaniam, M., Spelsberg, T. C., Wang, J., Wang, L. 2013; 43 (1): 258–69

    Abstract

    Bone marrow-derived macrophages (BMMs) treated with granulocyte-macrophage colony-stimulating factor (GM-CSF) or macrophage colony-stimulating factor (M-CSF), differentiate into GM-CSF-induced mouse bone marrow-derived macrophages (GM-BMMs) or M-CSF-induced mouse bone marrow-derived macrophages (M-BMMs), which have an M1 or M2 profile, respectively. GM-BMMs produce large amounts of proinflammatory cytokines and mediate resistance to pathogens, whereas M-BMMs produce antiinflammatory cytokines that contribute to tissue repair and remodeling. M-BMMs stimulated with lipopolysaccharide (LPS) are in an antiinflammatory state, with an IL-12(low) IL-10(high) phenotype. However, the regulation of this process remains unclear. Klf10 belongs to the family of Krüppel-like transcription factors and was initially described as a TGF-β inducible early gene 1. IL-12p40 is upregulated in LPS-stimulated M-BMMs from Klf10-deficient mice, but downregulated during Klf10 overexpression. Klf11, another member of the Krüppel-like factor family, can also repress the production of IL-12p40. Furthermore, Klf10 binds to the CACCC element of the IL-12p40 promoter and inhibits its transcription. We have therefore identified Klf10 as a transcription factor that regulates the expression of IL-12p40 in M-BMMs.

    View details for DOI 10.1002/eji.201242697

    View details for Web of Science ID 000313883200033

    View details for PubMedID 23065757

    View details for PubMedCentralID PMC3842096

  • MCPIP1 Down-Regulates IL-2 Expression through an ARE-Independent Pathway PLOS ONE Li, M., Cao, W., Liu, H., Zhang, W., Liu, X., Cai, Z., Guo, J., Wang, X., Hui, Z., Zhang, H., Wang, J., Wang, L. 2012; 7 (11): e49841

    Abstract

    IL-2 plays a key role in the survival and proliferation of immune cells, especially T lymphocytes. Its expression is precisely regulated at transcriptional and posttranscriptional level. IL-2 is known to be regulated by RNA binding proteins, such as tristetraprolin (TTP), via an AU-rich element (ARE) in the 3'-untranslated region (3'UTR) to influence the stability of mRNA. MCPIP1, identified as a novel RNase, can degrade IL-6, IL-12 and TNF-α mRNA by an ARE-independent pathway in the activation of macrophages. Here, we reported that MCPIP1 was induced in the activation of T lymphocytes and negatively regulated IL-2 gene expression in both mouse and human primary T lymphocytes through destabilizing its mRNA. A set of Luciferase reporter assay demonstrated that a non-ARE conserved element in IL-2 3'UTR, which formed a stem-loop structure, responded to MCPIP1 activity.RNA immunoprecipitation and Biotin pulldown experiments further suggested that MCPIP1 could modestly bind to IL-2 mRNA. Taken together, these data demonstrate that MCPIP1 down-regulates IL-2 via an ARE-independent pathway.

    View details for DOI 10.1371/journal.pone.0049841

    View details for Web of Science ID 000311821000120

    View details for PubMedID 23185455

    View details for PubMedCentralID PMC3504106