Identification of RIOK2 as a master regulator of human blood cell development
Identification of RIOK2 as a master regulator of human blood cell development
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DOI：
10.1038/s41590-021-01079-w
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发表时间：
2021-12-22
影响因子：
30.5
通讯作者：
Glimcher, Laurie H.
中科院分区：
文献类型：
--
作者：
Ghosh, Shrestha;Raundhal, Mahesh;Glimcher, Laurie H.
Ghosh等报道了显示非典型激酶RIOK 2作为含翼螺旋-转角-螺旋结构域的转录因子起作用的发现，所述转录因子调节人造血干细胞和祖细胞向红系、髓系和巨核细胞谱系的分化。RIOK 2可增强GATA 1和KLF 1的表达，同时抑制其他转录因子如RUNX 3、SPI 1和GATA 2的表达。贫血是衰老、慢性肾脏和炎症性疾病以及血液系统恶性肿瘤的主要并发症。然而，调控血细胞发育中造血分化的转录组学网络仍然不完全确定。在这里，我们报告的非典型激酶RIOK 2（右开放阅读框激酶2）是一个主转录因子（TF），不仅驱动红细胞分化，但也同时抑制巨核细胞和骨髓细胞在原代人类干细胞和祖细胞。我们的研究揭示了RIOK 2的以前未表征的翼螺旋-转角-螺旋DNA结合结构域和两个反式激活结构域，它们对调节关键的造血转录因子GATA 1、GATA 2、SPI 1、RUNX 3和KLF 1至关重要。这确立了RIOK 2作为调控人类造血分化的转录调控网络的组成部分。重要的是，在骨髓增生异常综合征、急性髓性白血病和慢性肾脏疾病中，RIOK 2 mRNA表达与这些TF和其他造血基因显著相关。对RIOK 2介导的转录途径的进一步研究应该产生纠正血液病中造血缺陷的治疗方法。
Ghosh et al. report findings showing that the atypical kinase RIOK2 functions as a winged helix-turn-helix domain containing transcription factor that regulates the differentiation of human hematopoietic stem and progenitor cells toward erythroid, myeloid and megakaryocytic lineages. RIOK2 enhances GATA1 and KLF1 expression, while suppressing other transcription factors like RUNX3, SPI1 and GATA2.Anemia is a major comorbidity in aging, chronic kidney and inflammatory diseases, and hematologic malignancies. However, the transcriptomic networks governing hematopoietic differentiation in blood cell development remain incompletely defined. Here we report that the atypical kinase RIOK2 (right open reading frame kinase 2) is a master transcription factor (TF) that not only drives erythroid differentiation, but also simultaneously suppresses megakaryopoiesis and myelopoiesis in primary human stem and progenitor cells. Our study reveals the previously uncharacterized winged helix-turn-helix DNA-binding domain and two transactivation domains of RIOK2 that are critical to regulate key hematopoietic TFs GATA1, GATA2, SPI1, RUNX3 and KLF1. This establishes RIOK2 as an integral component of the transcriptional regulatory network governing human hematopoietic differentiation. Importantly, RIOK2 mRNA expression significantly correlates with these TFs and other hematopoietic genes in myelodysplastic syndromes, acute myeloid leukemia and chronic kidney disease. Further investigation of RIOK2-mediated transcriptional pathways should yield therapeutic approaches to correct defective hematopoiesis in hematologic disorders.