Long intergenic non-coding RNA HOTAIRM1 regulates cell cycle progression during myeloid maturation in NB4 human promyelocytic leukemia cells
Long intergenic non-coding RNA HOTAIRM1 regulates cell cycle progression during myeloid maturation in NB4 human promyelocytic leukemia cells
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DOI：
10.4161/rna.28828
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发表时间：
2014-06-01
期刊：
影响因子：
4.1
通讯作者：
Newburger, Peter E.
中科院分区：
文献类型：
--
作者：
Zhang, Xueqing;Weissman, Sherman M.;Newburger, Peter E.
HOTAIRM1是人类HOXA基因簇中编码的一个长长的非编码RNA，其基因表达高度特异于成熟的髓系细胞。在NB4急性早幼粒细胞白血病细胞系中，HOTAIRM1基因的敲除抑制了全反式维甲酸(ATRA)诱导的粒细胞分化，导致了大量的未成熟和增殖的细胞，维持了细胞周期从G1期向S期的进展。相应地，HOTAIRM1基因敲除导致许多ATRA抑制的细胞周期和DNA复制基因的保留表达，并减弱ATRA对细胞表面白细胞激活、防御反应和其他成熟相关基因的诱导。基因敲除细胞对全反式维甲酸诱导的G1/S期细胞周期阻滞的抵抗伴随着ITGA4(CD49d)的保留表达和ITGAx(CD11c)的诱导减少。在这些整合素基因的表达模式中，细胞周期进程与时间动力学的耦合表明了控制从增殖期到粒细胞成熟的调控转换。此外，即使在没有全反式维甲酸处理的情况下，ITGAX也是少数几个在HOTAIRM1基因敲除时转录水平发生扰动的基因之一，这表明了一种直接的调控途径。这些结果表明，HOTAIRM1通过在基因表达水平上调节整合素控制的细胞周期进程，在髓系成熟过程中提供了一个调控环节。
HOTAIRM1 is a long intergenic non-coding RNA encoded in the human HOXA gene cluster, with gene expression highly specific for maturing myeloid cells. Knockdown of HOTAIRM1 in the NB4 acute promyelocytic leukemia cell line retarded all-trans retinoid acid (ATRA)-induced granulocytic differentiation, resulting in a significantly larger population of immature and proliferating cells that maintained cell cycle progression from G1 to S phases. Correspondingly, HOTAIRM1 knockdown resulted in retained expression of many otherwise ATRA-suppressed cell cycle and DNA replication genes, and abated ATRA induction of cell surface leukocyte activation, defense response, and other maturation-related genes. Resistance to ATRA-induced cell cycle arrest at the G1/S phase transition in knockdown cells was accompanied by retained expression of ITGA4 (CD49d) and decreased induction of ITGAX (CD11c). The coupling of cell cycle progression with temporal dynamics in the expression patterns of these integrin genes suggests a regulated switch to control the transit from the proliferative phase to granulocytic maturation. Furthermore, ITGAX was among a small number of genes showing perturbation in transcript levels upon HOTAIRM1 knockdown even without ATRA treatment, suggesting a direct pathway of regulation. These results indicate that HOTAIRM1 provides a regulatory link in myeloid maturation by modulating integrin-controlled cell cycle progression at the gene expression level.