Loss of RUNX1/AML1 arginine-methylation impairs peripheral T cell homeostasis

Shinsuke Mizutani, Tatsushi Yoshida, Xinyang Zhao, Stephen D. Nimer, Masafumi Taniwaki, Tsukasa Okuda

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

RUNX1 (previously termed AML1) 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. RUNX1 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 (PRMT1), which accounts for the majority of the type I PRMT activity in cells, methylates two arginine residues in RUNX1 (R206 and R210), and these modifications inhibit corepressor-binding to RUNX1 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 RUNX1. Homozygous Runx1KTAMK/KTAMK mice are born alive and appear normal during adulthood. However, Runx1KTAMK/KTAMK mice showed a reduction in CD3+ T lymphoid cells and a decrease in CD4+ T cells in peripheral lymphoid organs, in comparison to their wild-type littermates, leading to a reduction in the CD4+ to CD8+ T-cell ratio. These findings suggest that arginine-methylation of RUNX1 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 RUNX1 in the maintenance of the peripheral CD4+ T-cell population.

Original languageEnglish (US)
Pages (from-to)859-873
Number of pages15
JournalBritish Journal of Haematology
Volume170
Issue number6
DOIs
StatePublished - Sep 1 2015

Keywords

  • Leukaemia
  • Lymphocyte differentiation
  • Methylation
  • RUNX1
  • Transgenic mice models

ASJC Scopus subject areas

  • Hematology

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