Like transcription factors, microRNAs (miRNAs), a class of short regulatory non-coding RNAs known for their role in organ development, cellular differentiation, homeostasis, and function, have been extensively studied for their roles in controlling expression of different sets of genes that dictates the outcome of developmental transitions or cellular activation status of the immune cell populations. Previously, we have identified an important miRNA family, miR-23~27~24 clusters that play a diverse role in regulating the differentiation and function of multiple CD4+ helper T (Th) cell lineages as well as regulatory T (Treg) cells. Our work has shown that proper gene regulation by the miR-23~27~24 in CD4+ T cells is crucial to ensure the optimal balance between immunity and tolerance. Loss of miR-23~27~24 clusters in T cells resulted in dysregulated follicular helper (Tfh) cell responses when mice aged and severe Th2-driven airway inflammation upon challenges of different allergens. On the other hand, excessive expression of members of this miRNA family would also lead to the development of autoimmunity through both promoting the proinflammatory cytokine production by effector T (Teff) cells as well as impairing Treg cell homeostasis and function. Considering that many of the miRNA family targets identified in our previous work are also known to function in other immune cell populations, miR-23~27~24 clusters likely have a broader impact on the immune system beyond their role in regulating CD4+ T cell immunity. Here, we propose a multifaceted study employing genetic, biochemical, immunological approaches and whole animal experimentation to comprehensively examine the molecular and cellular mechanisms underlying miR-23 cluster-mediated immune regulation. In particular, while we will expand our efforts in studying this miRNA family in T cell immunity with a new focus on CD8+ T cell-mediated immune responses, we will also examine their potential new roles in both Tfh cells and B cells that are crucial for establishment of germinal center (GC) reactions and the resultant humoral immunity. Next, by combining RNA-seq, ChIP-seq approaches with newly developed IR-CLASH technology, we will explore the putative molecular mechanisms underlying miR-23 cluster-dependent immune regulation through identification of genes that are regulated in miR-23 cluster-dependent manner and through identification of targets that are directly controlled by miR-23 cluster. Collective, the over-arching goal of the current proposal is to not only establish a powerful model to dissect the molecular orchestration of cellular differentiation, function, and homeostasis in the adaptive immune system but also build a solid foundation with which to target the miR-23~27~24 family to combat infections and a wide array of human immunological diseases.
The proposed studies aim to facilitate basic understanding of the role of one important miRNA family in controlling the balance between immunity and tolerance and to explore the biological significance of such miRNA-mediated regulation in multiple immune cell subsets in the adaptive immune system. The results obtained from these studies will not only greatly extend our fundamental knowledge of miRNA-mediated immune regulation but also facilitate future translational research that aims at targeting miRNAs in the immune system as a therapeutic approach to treat different human immunological diseases.
| Mann, Mati; Mehta, Arnav; Zhao, Jimmy L et al. (2018) Author Correction: An NF-?B-microRNA regulatory network tunes macrophage inflammatory responses. Nat Commun 9:3338 |
| Cho, Sunglim; Lee, Hyang-Mi; Yu, I-Shing et al. (2018) Differential cell-intrinsic regulations of germinal center B and T cells by miR-146a and miR-146b. Nat Commun 9:2757 |
| Becher, Burkhard; Waisman, Ari; Lu, Li-Fan (2018) Conditional Gene-Targeting in Mice: Problems and Solutions. Immunity 48:835-836 |
| Liao, Hsin-Kai; Hatanaka, Fumiyuki; Araoka, Toshikazu et al. (2017) In Vivo Target Gene Activation via CRISPR/Cas9-Mediated Trans-epigenetic Modulation. Cell 171:1495-1507.e15 |
| Wu, Min-Zu; Cheng, Wei-Chung; Chen, Su-Feng et al. (2017) miR-25/93 mediates hypoxia-induced immunosuppression by repressing cGAS. Nat Cell Biol 19:1286-1296 |
| Cho, Sunglim; Wu, Cheng-Jang; Nguyen, Duc T et al. (2017) A Novel miR-24-TCF1 Axis in Modulating Effector T Cell Responses. J Immunol 198:3919-3926 |
| Wu, Cheng-Jang; Lu, Li-Fan (2017) MicroRNA in Immune Regulation. Curr Top Microbiol Immunol 410:249-267 |
| Glatman Zaretsky, Arielle; Konradt, Christoph; Dépis, Fabien et al. (2017) T Regulatory Cells Support Plasma Cell Populations in the Bone Marrow. Cell Rep 18:1906-1916 |
| Cruz, Leilani O; Hashemifar, Somaye Sadat; Wu, Cheng-Jang et al. (2017) Excessive expression of miR-27 impairs Treg-mediated immunological tolerance. J Clin Invest 127:530-542 |
| Shaw, Laura A; Bélanger, Simon; Omilusik, Kyla D et al. (2016) Id2 reinforces TH1 differentiation and inhibits E2A to repress TFH differentiation. Nat Immunol 17:834-43 |
Showing the most recent 10 out of 15 publications
