TRIM28 mediates chromatin modifications at the TCR? enhancer and regulates the development of T and natural killer T cells.

ABSTRACT: T-cell receptor-? (TCR?) rearrangement in CD4(+)CD8(+) double-positive immature thymocytes is a prerequisite for production of ?? T cells and invariant natural killer T cells. This developmental event is regulated by the TCR? enhancer (E?), 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? 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? and induces histone 3 lysine 4 trimethylation in the E? and distant regions of the TCR? locus, coupled with recruitment of Rag proteins. T-cell-conditional ablation of TRIM28 impaired TCR? gene rearrangement and compromised the development of ?? 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? locus.

SUBMITTER: Zhou XF 

PROVIDER: S-EPMC3523851 | biostudies-other | 2012 Dec

REPOSITORIES: biostudies-other