Malat1 as an evolutionarily conserved lncRNA, plays a positive role in regulating proliferation and maintaining undifferentiated status of early-stage hematopoietic cells.
Malat1 as an evolutionarily conserved lncRNA, plays a positive role in regulating proliferation and maintaining undifferentiated status of early-stage hematopoietic cells.
复制标题
DOI：
10.1186/s12864-015-1881-x
复制
发表时间：
2015-09-03
期刊：
影响因子：
4.4
通讯作者：
Liu FS
中科院分区：
文献类型：
--
作者：
Ma XY;Wang JH;Wang JL;Ma CX;Wang XC;Liu FS
转移相关肺腺癌转录因子1（Malat 1）是一个高度保守的长链非编码RNA（lncRNA）基因。研究表明，Malat 1在多种组织中大量表达，并通过调节基因表达和靶蛋白活性参与促进肿瘤生长和转移。然而，Malat 1在正常细胞增殖中的生物学功能及其调控机制尚不清楚。在本研究中，我们证实了Malat 1在20种哺乳动物中在广泛的进化距离上高度保守，并发现小鼠Malat 1在肝、肾、肺、心脏、睾丸、脾和脑组织中表达，而不在骨骼肌中表达。用全反式维甲酸（All-transRetinoicAcid，ATRA）处理EML细胞后，研究了Malat 1在EML细胞造血分化过程中的表达及调控。代表早期祖细胞的小鼠LRH（Lin-Rhodaminelow Hoechstlow）细胞显示出高水平的Malat 1表达，而代表晚期祖细胞的LRB（Lin-HoechstLow RhodamineBright）细胞没有检测到Malat 1的表达。敲除实验表明Malat 1的缺失抑制了EML细胞的增殖。在分化过程中，沿着Malat 1表达的下调，抑癌基因p53表达上调。有趣的是，我们在生物信息学工具的帮助下发现了两个p53结合基序，随后的染色质免疫沉淀（ChIP）测试证实了p53作为转录抑制因子与Malat 1的启动子结合。此外，我们证实了p53在EML细胞中的过表达导致Malat 1的下调。总之，本研究表明Malat 1在维持早期造血细胞的增殖潜力方面起着关键作用。除了其生物学功能外，本研究还揭示了p53介导的Malat 1表达在造血分化中的调控模式。我们的研究揭示了探索Malat 1的生物学作用，包括治疗意义，以抑制恶性细胞的增殖潜力。
The metastasis-associated lung adenocarcinoma transcription 1 (Malat1) is a highly conserved long non-coding RNA (lncRNA) gene. Previous studies showed that Malat1 is abundantly expressed in many tissues and involves in promoting tumor growth and metastasis by modulating gene expression and target protein activities. However, little is known about the biological function and regulation mechanism of Malat1 in normal cell proliferation. In this study we conformed that Malat1 is highly conserved across vast evolutionary distances amongst 20 species of mammals in terms of sequence, and found that mouse Malat1 expresses in tissues of liver, kidney, lung, heart, testis, spleen and brain, but not in skeletal muscle. After treating erythroid myeloid lymphoid (EML) cells with All-trans Retinoic Acid (ATRA), we investigated the expression and regulation of Malat1 during hematopoietic differentiation, the results showed that ATRA significantly down regulates Malat1 expression during the differentiation of EML cells. Mouse LRH (Lin-Rhodaminelow Hoechstlow) cells that represent the early-stage progenitor cells show a high level of Malat1 expression, while LRB (Lin − HoechstLow RhodamineBright) cells that represent the late-stage progenitor cells had no detectable expression of Malat1. Knockdown experiment showed that depletion of Malat1 inhibits the EML cell proliferation. Along with the down regulation of Malat1, the tumor suppressor gene p53 was up regulated during the differentiation. Interestingly, we found two p53 binding motifs with help of bioinformatic tools, and the following chromatin immunoprecipitation (ChIP) test conformed that p53 acts as a transcription repressor that binds to Malat1’s promoter. Furthermore, we testified that p53 over expression in EML cells causes down regulation of Malat1. In summary, this study indicates Malat1 plays a critical role in maintaining the proliferation potential of early-stage hematopoietic cells. In addition to its biological function, the study also uncovers the regulation pattern of Malat1 expression mediated by p53 in hematopoietic differentiation. Our research shed a light on exploring the Malat1 biological role including therapeutic significance to inhibit the proliferation potential of malignant cells.