Profiling the interactions of epigenetic regulators and their control of T cell states

Abstract

Characterizing the gene regulatory mechanisms that define distinct T cell states is essential to understanding T cell biology in health and disease. Despite advances in identifying transcriptional and epigenetic differences across T cell states, the regulators of these changes remain poorly defined. We performed a systems-level proteomic and genomic study to identify transcription factor (TF) and chromatin modifying cofactor (COF) complexes that might regulate cell state in resting, activated, and exhausted T cells. We used a high-throughput, protein-binding microarray-based approach called CoRec, to profile numerous COFs and identified unique TF-COF recruitment networks for each T cell state. In our study, some COFs are recruited specifically to TFs known to drive T cell state changes, including TFs implicated in T cell exhaustion. Exhaustion-specific recruitment of COFs suggests that these TFs may drive exhaustion through targeted alteration of epigenetic marks by these COFs. This alters expression of exhaustion-related genes and can create a functional change in T cell state. Additionally, by integrating our CoRec data with other methods, we examine how these TF-COF networks relate to chromatin accessibility and genome-wide chromatin marks. The CoRec method and its integration with other methods provides an exciting new approach for profiling cell-specific TF-COF complexes and allows us to better understand and identify the epigenetic regulators of T cell states.