טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentJacob Eyal
SubjectThe Role of the Lineage Specific Transcription Factors
and General Maintenance Machinery in Heritable
Cytokine Gene Expression in T Helper
(Th) Cells
DepartmentDepartment of Medicine
Supervisor Ms. Orly Avni
Full Thesis textFull thesis text - English Version


Abstract


When naive TH cells (CD4+) encounter an antigen, they can differentiate into effector or regulatory cells that have characteristic transcriptional profiles for cytokines and other genes. The effector lineages TH1, TH2, and TH17 are characterized by the expression of their signature cytokines IFNg, IL-4, and IL-17, respectively. IFNg exerts protective functions in microbial infections and is observed clinically in cases of autoimmune disease. IL-4 is strongly apparent in parasitic infections, and is associated with allergic reactions. IL-17 plays a role in eradication of extracellular pathogens, but inappropriate responses can also lead to autoimmunity. The cytokine transcription profiles of developing TH cells are maintained and induced appropriately following stimulation of differentiated cells. Epigenetic regulation combines several mechanisms to ensure the inheritance of transcriptional programs. In our search for factors propagating the differential TH phenotypes, we found that the expression of the polycomb group proteins (PcG proteins), whose role in maintaining gene silencing is well documented, was induced during development in TH1,TH2 and TH17 lineages. Nevertheless, the PcG proteins, YY1, Mel-18, Ring1A, Ezh2 and Eed, bound to the Il4 and Ifng loci in a differential pattern. In contrast to the prevailing dogma, the binding activity of the PcG proteins in differentiated TH cells was associated with cytokine transcription. The PcG proteins bound to the cytokine genes under resting conditions and their binding was induced dynamically following stimulation. By knocking down the PcG protein Mel-18 expression, we revealed that it functions as a part of a general-TH-machinery that positively regulates the expression of the hallmark cytokine genes in a selective manner in TH1, TH2 and TH17 cells, and in established TH cell lines. Moreover, Mel-18 was necessary for the recruitment of NFAT1 and T-bet to the IFN-γ promoter in TH1 cells. However, our results also indicate that the PcG proteins can act as transcriptional silencers, for example, of Tbx21 in TH17 cells. This dual function of the PcG proteins may participate in the mechanisms underlying the commitment and plasticity of the TH phenotypes. Considering the PcG proteins binding pattern at the cytokine genes and their known function in higher order folding of regulatory elements, we propose a model whereby the PcG proteins, in specific contexts, positively regulate the cytokine genes expression by mediating long-distance chromosomal interactions and through the recruitment of the acute transcription factors.