Loss of RUNX1/AML1 arginine-methylation impairs peripheral T cell homeostasis.
Loss of RUNX1/AML1 arginine-methylation impairs peripheral T cell homeostasis.
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DOI：
10.1111/bjh.13499
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发表时间：
2015-09
影响因子：
6.5
通讯作者：
Okuda T
中科院分区：
文献类型：
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作者：
Mizutani S;Yoshida T;Zhao X;Nimer SD;Taniwaki M;Okuda T
RUNX1（以前称为AML1）是人类白血病相关基因畸变的常见靶标，它编码核心结合因子转录因子复合物的dna结合亚基。RUNX1的表达对于最终的造血、稳定的血小板生成和正常淋巴细胞的发育至关重要。最近的研究表明，占细胞I型PRMT活性大部分的蛋白精氨酸甲基转移酶1 （PRMT1）甲基化RUNX1中的两个精氨酸残基（R206和R210），这些修饰抑制了RUNX1的协抑制子结合，从而增强了RUNX1的转录活性。为了阐明这些甲基化的生物学意义，我们在RUNX1中建立了具有不可甲基化、双精氨酸-赖氨酸（rtamr - ktamk）突变的新型敲入小鼠系。纯合子Runx1KTAMK/KTAMK小鼠出生时存活，成年后表现正常。然而，与野生型小鼠相比，Runx1KTAMK/KTAMK小鼠外周血淋巴样器官中CD3+ T淋巴样细胞和CD4+ T细胞减少，导致CD4+ / CD8+ T细胞比例降低。这些发现表明，rtamr基序RUNX1的精氨酸甲基化对于最终造血的发展和稳态血小板的产生是必不可少的，然而这种修饰会影响RUNX1在维持外周血CD4+ t细胞群中的作用。
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.