Division of Respiratory Medicine, Department of Pediatrics, and.
Department of Cell and Developmental Biology, UCSD, La Jolla, California, USA.
J Clin Invest. 2023 Jun 1;133(11):e165831. doi: 10.1172/JCI165831.
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.
红细胞增多症（EE）是患有慢性高山病（CMS，也称为 Monge 病）患者的主要特征，是导致成年早期发病率和死亡率升高的主要原因。我们利用独特的人群，一个生活在高海拔地区（秘鲁）表现出 EE，而另一个在同一海拔和地区的人群，没有 EE 的证据（非 CMS）。通过 RNA-Seq，我们确定并验证了一组长链非编码 RNA（lncRNAs）的功能，这些 lncRNAs 调节 Monge 病中的红细胞生成，但在非 CMS 人群中则没有。在这些 lncRNAs 中，缺氧诱导激酶介导的红细胞生成调节剂（HIKER）/LINC02228，我们发现它在 CMS 细胞的红细胞生成中起着关键作用。在缺氧条件下，HIKER 调节 CSNK2B（酪蛋白激酶 2 的调节亚基）。HIKER 的下调显著降低了 CSNK2B 的表达，从而显著减少了红细胞生成；此外，在 HIKER 下调的背景下上调 CSNK2B 可挽救红细胞生成缺陷。CSNK2B 的药理学抑制可显著减少红细胞集落，而 CSNK2B 在斑马鱼中的敲低导致血红蛋白化缺陷。我们得出结论，HIKER 调节 Monge 病中的红细胞生成，至少通过一个特定的靶标 CSNK2B（一种酪蛋白激酶）起作用。
