TRIM28 is an essential regulator of three-dimensional chromatin state underpinning CD8+ T cell activation

Abstract

T cell activation is accompanied by extensive changes in epigenome. However, the high-ordered chromatin organization underpinning CD8+ T cell activation is not fully known. Here, we show extensive changes in the three-dimensional genome during CD8+ T cell activation, associated with changes in gene transcription. We show that CD8+ T-cell-specific deletion of Trim28 in mice disrupts autocrine IL-2 production and leads to impaired CD8+ T cell activation in vitro and in vivo. Mechanistically, TRIM28 binds to regulatory regions of genes associated with the formation of chromosomal loops during activation. At the loop anchor regions, TRIM28-occupancy overlaps with that of CTCF, a factor known for defining the boundaries of topologically associating domains and for forming of the loop anchors. In the absence of Trim28, RNA Pol II and cohesin binding to these regions diminishes, and the chromosomal structure required for the active state is disrupted. These results thus identify a critical role for TRIM28-dependent chromatin topology in gene transcription in activated CD8+ T cells.