Cells must maintain some genes in a silent state while simultaneously keeping them poised for later expression. This property is critical for memory lymphocytes, however the mechanisms are unclear. Our prior findings showed that the Oct1 transcription factor is critical for poising the Il2 gene for the more rapid and stronger induction associated with secondary T cell stimulation. Oct1 is also critical for maintaining CD4 memory T cell numbers and function (unpublished data). However, our findings do not explain how Oct1 target genes remain transcriptionally poised in memory cells at long timepoints following T cell activation. Our central hypothesis is that OCA-B, a transcriptional co-activator known to dock with Oct1, prevents stable repression of multiple targets, to help maintain poised transcriptional states associated with immunological memory. This proposal will determine 1) the mechanism of gene poising by OCA-B at the Il2 gene locus, 2) the number and identity of target genes poised for later expression by OCA-B and 3) the capacity of OCA-B to regulate memory T cell states in vivo. Success with these experiments will identify the mechanism whereby CD4 memory T cells maintain critical genes in poised epigenetic states for later expression, and uncover a central regulator of immunological memory.
Specific Aim 1 : Determine the mechanism by which OCA-B maintains Il2 in a poised transcriptional state as part of the epigenetic program that maintains memory functionality.
Specific Aim 2 : Identify the target genes that utilize OCA-B to prevent stable repression.
Specific Aim 3 : Determine the in vivo consequences of OCA-B anti-repression.
This proposal combines analyses of gene poising by OCA-B (Aims 1 and 2) with dissection of the in vivo role of OCA-B in response to model pathogen infections (Aim 3), to test the hypothesis that gene poising by OCA-B is critical for the generation and maintenance of a memory response. The project is most relevant to T cell memory. Our preliminary findings demonstrating selective CD4 memory defects are unprecedented and reveal the potential to uncover a previously unappreciated cardinal element in the regulation of CD4 T cell memory responses (and the mechanism). To this can be added the potential to identify a widespread new mode poising target genes such as Il2. Therefore, we feel that the findings from experiments in the proposal are transformative.
|Tantin, Dean (2013) Oct transcription factors in development and stem cells: insights and mechanisms. Development 140:2857-66|