Explore FOXP3's role in the 3D organization of the genome. FOXP3 is a transcription factor expressed in regulatory T cells (Tregs) that are essential for the balanced function of the immune system. Tregs suppress the activity of autoreactive T cells; loss-of-function mutations in FOXP3 are casually liked to autoimmune diseases. The critical role of FOXP3 in the development and function of Tregs and the potential to harness Treg-based therapies have attracted much attention to the basic functional mechanism of FOXP3. Genome-wide analyses of FOXP3 binding sites (ChIP-on-chip and ChIP-seq) coupled with expression profiling revealed thousands of potential FOXP3- activated or repressed genes. Although some of these genes have subsequently been shown to be important to Treg, a mechanistic understanding between FOXP3-mediated gene expression and Treg function is still lacking. The proposed research intends to address this question by exploring FOXP3's role in the 3D organization of the genome. Previous structure/function studies of FOXP3 reveal an unexpected domain-swapping mechanism that is required for the suppression function of Tregs. Preliminary evidence suggests that the domain-swapped FOXP3 dimer may have evolved to bridge DNA, thereby mediating long-range chromatin interactions. This mode of transcription regulation has long been recognized and has gained considerable attention in recent years, but the molecular basis underlying the long-distance chromatin interactions has not been characterized. FOXP3 provides an ideal system to address this question, which in turn can yield insights into the mechanistic roles of FOXP3 in Tregs. The proposed research has the following three specific aims.
Aim 1 is to characterize the structural bases and molecular details of DNA bridging by FOXP3 by determining the structures of FOXP3 bound to DNA and its higher-order oligomer complex.
Aim 2 is to analyze DNA bridging by FOXP3 in solution at the biochemical level and test if DNA bridging by FOXP3 correlates with long distance gene-gene interactions in cells.
Aim 3 is to explore the effects of FOXP3 on the global architecture of the T cell genome using a newly developed chromosome conformation capture technology. The proposed studies seek to advance basic knowledge on how FOXP3 regulates specific gene expression via global reorganization of the 3D architecture of the genome. These studies will provide a new angle to study the mechanism by which FOXP3 confers the suppression function in Tregs and aid the development of Treg-based therapies in autoimmune/inflammatory diseases and immunotherapy of cancer.

Public Health Relevance

FOXP3 plays a critical role in the immune suppression program of regulatory T cells (Tregs) that are required for maintaining self-tolerance, manipulation of this program could provide strategies for Treg-based immunotherapy in autoimmunity and cancer. The proposed studies will help understand the mechanisms by which FOXP3 regulates specific gene expression in Tregs. This knowledge will in turn help to explore the therapeutic potential of FOXP3 and Tregs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI113009-04
Application #
9407290
Study Section
Macromolecular Structure and Function B Study Section (MSFB)
Program Officer
Ramachandra, Lakshmi
Project Start
2015-01-01
Project End
2019-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Southern California
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90033
Noridomi, Kaori; Watanabe, Go; Hansen, Melissa N et al. (2017) Structural insights into the molecular mechanisms of myasthenia gravis and their therapeutic implications. Elife 6:
Li, Jun; Dantas Machado, Ana Carolina; Guo, Ming et al. (2017) Structure of the Forkhead Domain of FOXA2 Bound to a Complete DNA Consensus Site. Biochemistry 56:3745-3753
Li, Jun; Jiang, Longying; Liang, Xujun et al. (2017) DNA-binding properties of FOXP3 transcription factor. Acta Biochim Biophys Sin (Shanghai) 49:792-799
Tjong, Harianto; Li, Wenyuan; Kalhor, Reza et al. (2016) Population-based 3D genome structure analysis reveals driving forces in spatial genome organization. Proc Natl Acad Sci U S A 113:E1663-72
Dai, Chao; Li, Wenyuan; Tjong, Harianto et al. (2016) Mining 3D genome structure populations identifies major factors governing the stability of regulatory communities. Nat Commun 7:11549
Wu, Daichao; Guo, Ming; Philips, Michael A et al. (2016) Crystal Structure of the FGFR4/LY2874455 Complex Reveals Insights into the Pan-FGFR Selectivity of LY2874455. PLoS One 11:e0162491
Galle-Treger, Lauriane; Suzuki, Yuzo; Patel, Nisheel et al. (2016) Nicotinic acetylcholine receptor agonist attenuates ILC2-dependent airway hyperreactivity. Nat Commun 7:13202
Chen, Yongheng; Chen, Chunxia; Zhang, Zhe et al. (2015) DNA binding by FOXP3 domain-swapped dimer suggests mechanisms of long-range chromosomal interactions. Nucleic Acids Res 43:1268-82
Duan, Yankun; Chen, Lin; Chen, Yongheng et al. (2014) c-Src binds to the cancer drug Ruxolitinib with an active conformation. PLoS One 9:e106225
Wang, Chen; Sang, Jiayan; Wang, Jiawei et al. (2013) Mechanistic insights revealed by the crystal structure of a histidine kinase with signal transducer and sensor domains. PLoS Biol 11:e1001493

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