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

5 Citations (Scopus)

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 Runx1<sup>KTAMK</sup><sup>/</sup><sup>KTAMK</sup> mice are born alive and appear normal during adulthood. However, Runx1<sup>KTAMK</sup><sup>/</sup><sup>KTAMK</sup> mice showed a reduction in CD3<sup>+</sup> T lymphoid cells and a decrease in CD4<sup>+</sup> T cells in peripheral lymphoid organs, in comparison to their wild-type littermates, leading to a reduction in the CD4<sup>+</sup> to CD8<sup>+</sup> 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<sup>+</sup> 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

Fingerprint

Methylation
Arginine
Homeostasis
Hematopoiesis
T-Lymphocytes
Protein-Arginine N-Methyltransferases
Core Binding Factors
Lymphocytes
Thrombopoiesis
Co-Repressor Proteins
Lysine
Leukemia
Transcription Factors
Blood Platelets
Maintenance
Mutation
DNA
Population
Genes

Keywords

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

ASJC Scopus subject areas

  • Hematology

Cite this

Loss of RUNX1/AML1 arginine-methylation impairs peripheral T cell homeostasis. / Mizutani, Shinsuke; Yoshida, Tatsushi; Zhao, Xinyang; Nimer, Stephen D; Taniwaki, Masafumi; Okuda, Tsukasa.

In: British Journal of Haematology, Vol. 170, No. 6, 01.09.2015, p. 859-873.

Research output: Contribution to journalArticle

Mizutani, Shinsuke ; Yoshida, Tatsushi ; Zhao, Xinyang ; Nimer, Stephen D ; Taniwaki, Masafumi ; Okuda, Tsukasa. / Loss of RUNX1/AML1 arginine-methylation impairs peripheral T cell homeostasis. In: British Journal of Haematology. 2015 ; Vol. 170, No. 6. pp. 859-873.
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