Long noncoding RNA HIKER regulates erythropoiesis in Monge's disease via CSNK2B.
Long noncoding RNA HIKER regulates erythropoiesis in Monge's disease via CSNK2B.
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DOI：
10.1172/jci165831
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发表时间：
2023-06-01
影响因子：
15.9
通讯作者：
Haddad, Gabriel G.
中科院分区：
文献类型：
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作者：
Azad, Priti;Zhou, Dan;Tu, Hung-Chi;Villafuerte, Francisco C.;Traver, David;Rana, Tariq M.;Haddad, Gabriel G.
过度红细胞增多症（EE）是患有慢性高山病（CMS，也称为Monge病）的患者的主要标志，并且是成年早期的主要发病率甚至死亡率的原因。我们利用了独特的人群，一个生活在高海拔（秘鲁）显示EE，与另一个人口，在相同的海拔和地区，没有显示EE的证据（非CMS）。通过RNA-Seq，我们鉴定并验证了一组长链非编码RNA（lncRNA）在Monge病中调节红细胞生成的功能，但不在非CMS人群中。在这些lncRNA中，缺氧诱导的激酶介导的红细胞生成调节因子（HIKER）/LINC 02228，我们显示其在CMS细胞中的红细胞生成中起关键作用。在缺氧条件下，HIKER调节CSNK 2B（酪蛋白激酶2的调节亚基）。HIKER的下调下调CSNK 2B，显著减少红细胞生成;此外，在HIKER下调的背景下CSNK 2B的上调挽救了红细胞生成缺陷。CSNK 2B的药理学抑制显著减少红系细胞集落，并且斑马鱼中CSNK 2B的敲低导致血红蛋白化缺陷。我们的结论是，HIKER调节红细胞生成在蒙赫氏病，并通过至少一个特定的目标，CSNK 2B，酪蛋白激酶的行为。
Excessive erythrocytosis (EE) is a major hallmark of patients suffering from chronic mountain sickness (CMS, also known as Monge’s disease) and is responsible for major morbidity and even mortality in early adulthood. We took advantage of unique populations, one living at high altitude (Peru) showing EE, with another population, at the same altitude and region, showing no evidence of EE (non-CMS). Through RNA-Seq, we identified and validated the function of a group of long noncoding RNAs (lncRNAs) that regulate erythropoiesis in Monge’s disease, but not in the non-CMS population. Among these lncRNAs is hypoxia induced kinase-mediated erythropoietic regulator (HIKER)/LINC02228, which we showed plays a critical role in erythropoiesis in CMS cells. Under hypoxia, HIKER modulated CSNK2B (the regulatory subunit of casein kinase 2). A downregulation of HIKER downregulated CSNK2B, remarkably reducing erythropoiesis; furthermore, an upregulation of CSNK2B on the background of HIKER downregulation rescued erythropoiesis defects. Pharmacologic inhibition of CSNK2B drastically reduced erythroid colonies, and knockdown of CSNK2B in zebrafish led to a defect in hemoglobinization. We conclude that HIKER regulates erythropoiesis in Monge’s disease and acts through at least one specific target, CSNK2B, a casein kinase.
影响因子：
5.6
作者：
Wang, Saini;Yadav, Anil Kumar;Han, Jin-Yi;Ahn, Keun Soo;Jang, Byeong-Churl
通讯作者：
Jang, Byeong-Churl