Hierarchical interactions between chromatin remodeling transcription factors define the epigenetic landscape of antiviral T cells [scATAC]

T cell activation induces rapid proliferative expansion and the acquisitions of specialized effector functions that enable protection against invading pathogens. While a multitude of transcription factors (TFs) have been implicated in the regulation of T cell activation, it remains largely unclear how their functions are organized and integrated at the genomic level. Here, we leveraged naturally occurring TF binding site polymorphisms in wild derived inbred mice to identify the most critical “heavy lifters” that shape the epigenetic landscape of naïve and activated antiviral CD4 and CD8 T cells. We found that representative members of Ets, Runx, and TCF/Lef families occupied the vast majority of accessible chromatin regions and that interactions between them were associated with distinct epigenetic responses to T cell activation. We define prevalent genomic functions of Ets1, Runx1, and TCF1 as “housekeeper”, “universal amplifier”, and “placeholder”, respectively. Interestingly, regulatory elements associated with some of the most strongly induced and well-characterized immune response genes showed a non-canonical pattern of TF recruitment. Overall design: The project studied the single cell chromatin accessibility of CD8/CD4 T cell in response to virial infection. CD4 and CD8 T cells were sorted from pooled splenocytes of 3 LCMV Armstrong infected (B6/Cast) F1 mice on day 7 post infection.