The role of the transcriptional repressor YY1 in immunoregulatory gp96-mediated immune responses

Abstract

Abstract Heat shock protein (HSP)-mediated immune responses encompass both antigen-specific pro-inflammatory responses as well as non-antigen specific regulatory responses. The type of immune response primed depends on antigen presenting cell engaged by the HSP. Classical dendritic cells (cDCs) and macrophages elicit inflammatory responses in response to immunogenic HSPs such as gp96, whereas plasmacytoid dendritic cells (pDCs) induce regulatory responses. We have previously shown that NRP1 is in part responsible for the difference between these subsets. Gp96 signaling increases NRP1 expression on pDCs but not cDCs. This increased expression drives pDC-Treg interactions and results in activated Tregs. Increased NRP1 expression in pDCs is dependent on DNA methylation and an area of differential methylation has been identified in intron 2 of NRP1. Within this region of intron 2, bisulfite sequencing was used to look for specific sites of methylation. Intron 2 includes 2 CpG sites which show increased methylation in pDCs following stimulation with gp96. In the same region of these CpG sites, there is a consensus sequence for the transcriptional repressor YY1. We are investigating the role of YY1 as an inhibitor of NRP1 transcription, whose binding is blocked by methylation at intron 2. Using ChIP assays, siRNA knockdowns and cell imaging studies we will determine the role of YY1 in gp96-mediated immunoregulatory responses.