A Histone Methyltransferase ESET Is Critical for T Cell Development

Area of Science:

• Immunology
• Epigenetics
• Molecular Biology

Background:

• Histone methyltransferases regulate gene expression through epigenetic modifications.
• ESET/SETDB1 catalyzes histone 3 lysine 9 trimethylation (H3K9me3) and is vital for embryonic stem cell function.
• The role of ESET in immune system development, particularly T cell maturation, remains uncharacterized.

Purpose of the Study:

• To investigate the function of ESET in T cell development within the thymus.
• To elucidate the molecular mechanisms underlying ESET's role in thymocyte differentiation and function.

Main Methods:

• Generation of thymocyte-specific ESET-deficient mice (ESET(-/-)).
• Flow cytometry analysis of thymocyte populations and apoptosis.
• Assessment of T cell receptor (TCR)-induced extracellular signal-regulated kinase (ERK) activation.
• Genome-wide mRNA expression profiling and H3K9me3 analysis.
• Genetic manipulation to deplete FcγRIIB in ESET(-/-) thymocytes.

Main Results:

• Thymocyte-specific deletion of ESET resulted in impaired T cell development, with a severe impact on CD8 lineage cells.
• ESET deficiency led to increased apoptosis of CD8 single-positive thymocytes and inhibited TCR-induced ERK activation.
• Genome-wide analyses revealed ESET regulates numerous genes in thymocytes, including the ectopic and strong expression of FcγRIIB.
• Genetic depletion of FcγRIIB rescued ERK activation and partially restored positive selection in ESET(-/-) thymocytes.

Conclusions:

• ESET is identified as the first H3K9 trimethyltransferase critical for T cell development.
• Impaired T cell development in ESET(-/-) mice is partly attributed to aberrant FcγRIIB expression, which inhibits ERK signaling.
• ESET plays a significant role in regulating thymocyte differentiation and survival through epigenetic control of gene expression.