TRIM28 mediates chromatin modifications at the TCRα enhancer and regulates the development of T and natural killer T cells

T-cell receptor-alpha (TCR alpha) rearrangement in CD4(+) CD8(+) double-positive immature thymocytes is a prerequisite for production of alpha beta T cells and invariant natural killer T cells. This developmental event is regulated by the TCR alpha enhancer (E alpha), which induces chromatin modification and recruitment of the recombination-activating proteins Rag1 and Rag2. However, the molecular mechanism underlying the activation and long-range action of E alpha remains incompletely understood. We show here that the chromatin-modifying factor TRIM28 is highly expressed in double-positive thymocytes and persistently phosphorylated at serine 473. TRIM28 binds to E alpha and induces histone 3 lysine 4 trimethylation in the E alpha and distant regions of the TCR alpha locus, coupled with recruitment of Rag proteins. T-cell-conditional ablation of TRIM28 impaired TCRa gene rearrangement and compromised the development of alpha beta T cells and invariant natural killer T cells. These findings establish TRIM28 as a unique regulator of thymocyte development and highlight an epigenetic mechanism involving TRIM28-mediated active chromatin modification in the TCR alpha locus.