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 suppresses 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 (e.g. transplantation rejection) 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 reveal 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 adress 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 basis of DNA bridging by FOXP3 by determining the structures of FOXP3 bound to DNA and its higher-order oligomer complex.
Aim 2 is to test if FOXP3 can directly bridge DNA at the biochemical level and if FOXP3 can regulates long distance gene-gene interactions inside 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 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 seek to understand the mechanisms by which FOXP3 regulates specific gene expression in Tregs. This knowledge will help to explore the therapeutic potential of Treg-mediated immune suppression.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
High Priority, Short Term Project Award (R56)
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Macromolecular Structure and Function B Study Section (MSFB)
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Lapham, Cheryl K
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University of Southern California
Schools of Arts and Sciences
Los Angeles
United States
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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
Chen, Yongheng; Zhang, Xiaojun; Dantas Machado, Ana Carolina et al. (2013) Structure of p53 binding to the BAX response element reveals DNA unwinding and compression to accommodate base-pair insertion. Nucleic Acids Res 41:8368-76