BACKGROUND The Runt-related transcription factors (Runx) are a family of evolutionarily conserved transcriptional regulators that play multiple roles in the developmental control of various cell types. Among the three mammalian Runx proteins, Runx1 is essential for definitive hematopoiesis and its dysfunction leads to human leukemogenesis. There are two promoters, distal (P1) and proximal (P2), in the Runx1 gene, which produce two Runx1 isoforms with distinct N-terminal amino acid sequences, P1-Runx1 and P2-Runx1. However, it remains unclear whether P2-Runx specific N-terminal sequence have any specific function for Runx1 protein. RESULTS To address the function of the P2-Runx1 isoform, we established novel mutant mouse models in which the translational initiation AUG (+1) codon for P2-Runx1 isoform was modulated. We found that a truncated P2-Runx1 isoform is translated from a downstream non-canonical AUG codon. Importantly, the truncated P2-Runx1 isoform is sufficient to support primary hematopoiesis, even in the absence of the P1-Runx1 isoform. Furthermore, the truncated P2-Runx1 isoform was able to restore defect in basophil development caused by loss of the P1-Runx1 isoform. The truncated P2-Runx1 isoform was more stable than the canonical P2-Runx1 isoform. CONCLUSIONS Our results demonstrate that the N-terminal sequences specific for P2-Runx1 are dispensable for Runx1 function, and likely serve as a de-stabilization module to regulate Runx1 production.

中文翻译：

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对于Runx1功能，两个Runx1同工型中唯一的N末端序列是必不可少的。

背景技术矮子相关转录因子（Runx）是进化上保守的转录调节子家族，其在各种细胞类型的发育控制中起多种作用。在三种哺乳动物Runx蛋白中，Runx1对于确定的造血作用必不可少，其功能障碍会导致人类白血病的发生。Runx1基因中有两个启动子，远端（P1）和近端（P2），它们产生具有不同N末端氨基酸序列的两个Runx1同工型P1-Runx1和P2-Runx1。但是，尚不清楚P2-Runx特异的N端序列是否对Runx1蛋白具有任何特定的功能。结果为了解决P2-Runx1同工型的功能，我们建立了新型突变小鼠模型，其中对P2-Runx1同工型的翻译起始AUG（+1）密码子进行了调节。我们发现，截短的P2-Runx1亚型是从下游非规范AUG密码子翻译而来的。重要的是，即使没有P1-Runx1亚型，截短的P2-Runx1亚型也足以支持原发性造血。此外，截短的P2-Runx1亚型能够恢复由于P1-Runx1亚型的丧失而导致的嗜碱性粒细胞发育缺陷。截短的P2-Runx1亚型比规范的P2-Runx1亚型更稳定。结论我们的结果表明，P2-Runx1的N末端序列对于Runx1功能是必不可少的，并且可能充当去稳定模块来调节Runx1的产生。此外，截短的P2-Runx1亚型能够恢复由于P1-Runx1亚型的丧失而导致的嗜碱性粒细胞发育缺陷。截短的P2-Runx1亚型比规范的P2-Runx1亚型更稳定。结论我们的结果表明，P2-Runx1的N末端序列对于Runx1功能是必不可少的，并且可能充当去稳定模块来调节Runx1的产生。此外，截短的P2-Runx1亚型能够恢复由于P1-Runx1亚型的丧失而导致的嗜碱性粒细胞发育缺陷。截短的P2-Runx1亚型比规范的P2-Runx1亚型更稳定。结论我们的结果表明，P2-Runx1的N末端序列对于Runx1功能是必不可少的，并且可能充当去稳定模块来调节Runx1的产生。