Hierarchical Regulation of the Resting and Activated T Cell Epigenome by Major Transcription Factor Families

T cell activation, a key early event in the adaptive immune response, is subject to elaborate transcriptional control. Here, we examined how the activities of eight major transcription factor (TF) families are integrated to shape the epigenome of naïve and activated CD4 and CD8 T cells. By leveraging extensive polymorphisms in evolutionarily divergent mice, we identified the “heavy lifters” positively influencing chromatin accessibility. Members of Ets, Runx, and TCF/Lef TF families occupied the vast majority of accessible chromatin regions, acting as “housekeepers”, “universal amplifiers”, and “placeholders”, respectively, at sites that maintained or gained accessibility upon T cell activation. Additionally, a small subset of strongly induced immune response genes displayed a non-canonical TF recruitment pattern. Our study provides a key resource and foundation for the understanding of transcriptional and epigenetic regulation in T cells and offers a new perspective on the hierarchical interactions between critical TFs.