Long noncoding RNA CCDC26 as a modulator of transcriptional switching between fetal and embryonic globins
Long noncoding RNA CCDC26 as a modulator of transcriptional switching between fetal and embryonic globins
复制标题
DOI：
10.1016/j.bbamcr.2020.118931
复制
发表时间：
2021-03-01
影响因子：
5.1
通讯作者：
Ishida, Atsuhiko
中科院分区：
文献类型：
--
作者：
Hirano, Tetsuo;Tsuruda, Tomomi;Ishida, Atsuhiko
CCDC26基因被认为编码一种与急性髓系白血病和其他癌症相关的功能性非编码RNA。然而，对CCDC26的生理作用的研究很少。此前，我们曾报道CCDC26通过K562白血病细胞及其衍生的CCDC26基因敲除(KD)细胞，通过KIT调节白血病细胞的增殖和细胞死亡。在此，我们提出了CCDC26在红系细胞分化中的新作用。我们发现在氯化血红素诱导分化过程中，CCDC26-KD细胞与K562对照细胞相比，胚胎(epsilon-和zeta-)珠蛋白的表达明显上调。相反，在原始K562细胞中表达的主要珠蛋白--胎儿型γ-珠蛋白的表达减少。这些珠蛋白基因表达的变化主要发生在转录水平，在CCDC26-KD细胞中，成体(β、β)珠蛋白的转录受到显著抑制。将外源CCDC26重新导入CCDC26-KD细胞，恢复了胚胎珠蛋白的低水平表达。这些结果表明，CCDC26在红系细胞分化过程中参与了珠蛋白基因转录的转换。CCDC26-KD细胞和对照细胞的表达谱表明，转录调控因子FOG-2是CCDC26相关调控的候选调节因子。我们发现这两种胚胎珠蛋白在FOG-2-KD K562细胞中都被转录激活。KIT抑制剂ISCK03抑制K562细胞中血红蛋白的产生，但不影响珠蛋白基因的转录。综上所述，负责CCDC26对珠蛋白转录调控的是FOG-2，而不是KIT。
The CCDC26 gene is considered to encode a functional noncoding RNA associated with acute myeloid leukemia and other cancers. However, investigations into the physiological roles of CCDC26 are rare. Previously, we reported that CCDC26 regulated proliferation and cell death of leukemia cells through KIT, a receptor tyrosine kinase, by using K562 leukemia cells and their derivative CCDC26-knockdown (KD) cells. Here we propose a new role of CCDC26 in the differentiation of erythroid cells. We showed that expression of embryonic (epsilon- and zeta-) globins was markedly upregulated in CCDC26-KD cells compared with K562 control cells during hemin-induced differentiation. In contrast, expression of fetal-type gamma-globin, a major globin expressed in original K562 cells, was decreased. These changes in the expression of globin genes mainly took place at the transcriptional level, with significant suppression of transcription of adult (beta-, delta-) globins in CCDC26-KD cells. Re-introduction of exogenous CCDC26 into the CCDC26-KD cells recovered low-level expression of the embryonal globins. These results suggest CCDC26 has a role in switching transcription of globin genes in the differentiation of erythroid cells. The expression profile of the CCDC26-KD cells and control cells suggests FOG-2, a transcriptional modulator, as a candidate for a mediator of the CCDC26-associated regulation. We showed that both embryonic globins were transcriptionally activated in FOG-2-KD K562 cells. The KIT inhibitor ISCK03 suppressed the production of hemoglobin in K562 cells but did not affect transcription of globin genes. To summarize, FOG-2, but not KIT, is responsible for globin transcriptional regulation by CCDC26.