ESET/SETDB1, one of the major histone methyltransferases, catalyzes histone 3 lysine 9 (H3K9) trimethylation. ESET is critical for suppressing expression of retroviral elements in embryonic stem cells; however, its role in the immune system is not known.We found that thymocyte-specific deletion of ESET caused impaired T cell development, with CD8 lineage cells being most severely affected. Increased apoptosis of CD8 single-positive cells was observed, and TCR-induced ERK activation was severely inhibited in ESET2/2 thymocytes. Genome-wide comprehensive analysis of mRNA expression and H3K9 trimethylation revealed that ESET regulates expression of numerous genes in thymocytes. Among them, FcgRIIB, whose signaling can inhibit ERK activation, was strongly and ectopically expressed in ESET2/2 thymocytes. Indeed, genetic depletion of FcgRIIB in ESET2/2 thymocytes rescued impaired ERK activation and partially restored defective positive selection in ESET2/2 mice. Therefore, impaired T cell development in ESET2/2 mice is partly due to the aberrant expression of FcgRIIB. Collectively, to our knowledge, we identify ESET as the first trimethylated H3K9 histone methyltransferase playing a crucial role in T cell development.
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