title: Loss of RUNX1/AML1 arginine-methylation impairs peripheral T cell homeostasis.
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(KTAMK) (/) (KTAMK) mice are born alive and appear normal during adulthood. However, Runx1(KTAMK) (/) (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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan.|Division of Haematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Mizutani
authors.affiliation: Department of Biochemistry and Molecular Biology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan.
authors.forename: Tatsushi
authors.initials: T
authors.lastname: Yoshida
authors.affiliation: Department of Biochemistry & Molecular Genetics, University of Alabama, Birmingham, AL, USA.
authors.forename: Xinyang
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Nimer
authors.affiliation: Division of Haematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Taniwaki
authors.affiliation: Department of Biochemistry and Molecular Biology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan.
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Okuda
mesh_terms: D000483:Alleles; D020816:Amino Acid Motifs; D000818:Animals; D001120:Arginine / Q000378:metabolism*; D018791:CD4 Lymphocyte Count; D050676:Core Binding Factor Alpha 2 Subunit / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D053595:Embryonic Stem Cells / Q000378:metabolism; D055879:Gene Knock-In Techniques; D023061:Gene Order; D018390:Gene Targeting; D005822:Genetic Vectors / Q000235:genetics; D005838:Genotype; D005854:Germ Cells / Q000378:metabolism; D006410:Hematopoiesis / Q000235:genetics; D006801:Humans; D008745:Methylation; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D038042:Myelopoiesis / Q000235:genetics; D010641:Phenotype; D013601:T-Lymphocytes / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D001120:Arginine
keywords: RUNX1; leukaemia; lymphocyte differentiation; methylation; transgenic mice models