טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentBoyko Yulia
SubjectAspects of the Mechanism Underlying the Bi-Functional
Role of Polycomb Group Proteins in T Helper (CDA+)
Cells
DepartmentDepartment of Medicine
Supervisor Ms. Orly Avni
Full Thesis textFull thesis text - English Version


Abstract

T helper (Th) cells have a crucial function in the immune response. Following antigen recognition Th cells can differentiate into several effector lineages, with distinctive expression profile of cytokines, and consequently, with unique anti-microbial or anti-parasitic functions. The differentiation processes of Th cells are accompanied by major epigenetic changes that enable the maintenance of the transcriptional profiles in differentiated cells, but at the same time preserve a certain level of plasticity that may allow adaptation to new immunological challenges. Previously, it was found in my lab that the polycomb group (PcG) proteins are associated with active cytokine genes differentially in Th1 and Th2 cells. Considering the known function of the PcG proteins as transcriptional repressors, these results raised the feasible scenario in which PcG proteins restrain overexpression of the active/accessible cytokine genes. However, further knockdown experiments were more compatible with the idea that PcG proteins can function also as transcriptional activators. I found that the binding activity of the PcG proteins in Th17 to the hallmark cytokine gene is also associated with gene expression. Since our data suggest that the PcG proteins posses a dual function in differentiated Th cells, I asked whether PcG proteins repress the expression of the opposing cytokine gene, e.g. Ifng in Th2 cells. I found indeed that Mel-18 was associated with a potential silencer on the Ifng locus in Th2 cells. However, since silencing of Mel-18 did not de-repress the expression of Ifng, even in the presence of the Th1 polarizing cytokines, I hypothesized that the reason might be that PcG proteins are required for both repression and activation of cytokine genes. In order to study the mechanisms underlying the dual function of PcG proteins, I tried to identify potential Ezh2 isoforms in Th cells that may selectively participate in either activation or repression. Interestingly, the two isoforms that I recognized are different in the presence of a cysteine-rich-domain that in general is associated with protein-protein interactions. It is tempting to speculate therefore that this region may affect the function of Ezh2 through differential interactions. My work also strengthened the hypothesis that NFAT is required for the recruitment of PcG proteins to the active cytokine genes, however, I refuted the possibility that NFAT is involved in promoting the H3K27Ac mark at the active cytokine gene promoters. My preliminary data suggest that the trithorax protein MLL1 is required to establish the H3K27Ac at the Il4 promoter.