Transcription factor FOXP3 is essential to establish a functional regulatory T cell (Treg) phenotype. Detailed studies have demonstrated that FOXP3 and interacting proteins reinforce their own expression, and activate the downstream FOXP3-dependent transcriptional program. In the preliminary data for this application, we show that FOXP3 directly interacts with hnRNPF (heterogeneous nuclear ribonucleoprotein F) to modulate hnRNPF-mediated RNA alternative splicing. In an immune response, wide spread changes in splicing patterns regulate lymphocyte function and responses to antigen. We hypothesize that FOXP3 modulates Treg development and function through modulating hnRNPF-mediated RNA alternative splicing. We will test this hypothesis with the following specific aims: 1. Define the mechanism for FOXP3 in modulating mRNA alternative splicing through its interaction with hnRNPF. 2. Define the ability of hnRNPF to modulate Treg differentiation and immune-mediated inflammation. Our overall goal for this application is to define, at the molecular level, how interaction between FOXP3 and hnRNPF affects hnRNPF's ability to bind to and modulate RNA alternative splicing. We will also define the effects of perturbed hnRNPF expression on Treg differentiation and function in autoimmune colitis. The information learned from these studies will provide a greater understanding of the role of FOXP3 in Treg differentiation and function, and how altered alternative splicing in Tregs affects immune-mediated inflammatory diseases.
For many years transcription factor FOXP3 has been known to regulate transcription of its target genes to control regulatory T cell development and function We present preliminary data that FOXP3 directly interacts with hnRNPF to regulate RNA alternative splicing. In this proposal we will study the molecular mechanism for FOXP3 to interact with hnRNPF and regulate RNA alternative splicing, providing new information about how this interaction modulates regulatory T cell differentiation and development, and how perturbed interaction between them affects the development of immune-mediated inflammation.
| Du, Jianguang; Wang, Qun; Ziegler, Steven F et al. (2018) FOXP3 interacts with hnRNPF to modulate pre-mRNA alternative splicing. J Biol Chem 293:10235-10244 |
