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Loss of RUNX 1/ AML 1 arginine‐methylation impairs peripheral T cell homeostasis
Author(s) -
Mizutani Shinsuke,
Yoshida Tatsushi,
Zhao Xinyang,
Nimer Stephen D.,
Taniwaki Masafumi,
Okuda Tsukasa
Publication year - 2015
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.13499
Subject(s) - runx1 , biology , haematopoiesis , core binding factor , arginine , transcription factor , microbiology and biotechnology , stem cell , genetics , gene , amino acid
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.