A Histone Methyltransferase ESET Is Critical for T Cell Development.
Shoichi TakikitaRyunosuke MuroToshiyuki TakaiTakeshi OtsuboYuki I KawamuraTaeko DohiHiroyo OdaMasayuki KitajimaKenshiro OshimaMasahira HattoriTakaho A EndoTetsuro ToyodaJohn WeisYoichi ShinkaiHarumi SuzukiPublished in: Journal of immunology (Baltimore, Md. : 1950) (2016)
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 ESET(-/-) thymocytes. Genome-wide comprehensive analysis of mRNA expression and H3K9 trimethylation revealed that ESET regulates expression of numerous genes in thymocytes. Among them, FcγRIIB, whose signaling can inhibit ERK activation, was strongly and ectopically expressed in ESET(-/-) thymocytes. Indeed, genetic depletion of FcγRIIB in ESET(-/-) thymocytes rescued impaired ERK activation and partially restored defective positive selection in ESET(-/-) mice. Therefore, impaired T cell development in ESET(-/-) mice is partly due to the aberrant expression of FcγRIIB. Collectively, to our knowledge, we identify ESET as the first trimethylated H3K9 histone methyltransferase playing a crucial role in T cell development.
Keyphrases
- genome wide
- dna methylation
- signaling pathway
- poor prognosis
- cell cycle arrest
- induced apoptosis
- cell proliferation
- healthcare
- endoplasmic reticulum stress
- cell death
- type diabetes
- single cell
- gene expression
- adipose tissue
- diabetic rats
- binding protein
- regulatory t cells
- immune response
- transcription factor
- endothelial cells
- long non coding rna