Loss of RUNX 1/ AML 1 arginine‐methylation impairs peripheral T cell homeostasis

Summary RUNX 1 (previously termed AML 1 ) is a frequent target of human leukaemia‐associated gene aberrations, and it encodes the DNA ‐binding subunit of the Core‐Binding Factor transcription factor complex. RUNX 1 expression is essential for the initiation of definitive haematopoiesis, for steady‐state thrombopoiesis, and for normal lymphocytes development. Recent studies revealed that protein arginine methyltransferase 1 ( PRMT 1), which accounts for the majority of the type I PRMT activity in cells, methylates two arginine residues in RUNX 1 (R206 and R210), and these modifications inhibit corepressor‐binding to RUNX 1 thereby enhancing its transcriptional activity. In order to elucidate the biological significance of these methylations, we established novel knock‐in mouse lines with non‐methylable, double arginine‐to‐lysine ( RTAMR ‐to‐ KTAMK ) mutations in RUNX 1. Homozygous Runx1 KTAMK/KTAMK mice are born alive and appear normal during adulthood. However, Runx1 KTAMK/KTAMK mice showed a reduction in CD 3 + T lymphoid cells and a decrease in CD 4 + T cells in peripheral lymphoid organs, in comparison to their wild‐type littermates, leading to a reduction in the CD 4 + to CD 8 + T‐cell ratio. These findings suggest that arginine‐methylation of RUNX 1 in the RTAMR ‐motif is dispensable for the development of definitive haematopoiesis and for steady‐state platelet production, however this modification affects the role of RUNX 1 in the maintenance of the peripheral CD 4 + T‐cell population.