Upregulation of lncRNA MEG3 Promotes Osteogenic Differentiation of Mesenchymal Stem Cells From Multiple Myeloma Patients By Targeting BMP4 Transcription
Upregulation of lncRNA MEG3 Promotes Osteogenic Differentiation of Mesenchymal Stem Cells From Multiple Myeloma Patients By Targeting BMP4 Transcription
复制标题
lncRNA MEG3的上调通过靶向BMP4转录促进多发性骨髓瘤患者间充质干细胞的成骨分化
DOI：
10.1002/stem.1989
复制
发表时间：
2015-06-01
期刊：
影响因子：
5.2
通讯作者：
Li, Bingzong
中科院分区：
文献类型：
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作者：
Zhuang, Wenzhuo;Ge, Xueping;Li, Bingzong
多发性骨髓瘤（MM）的特征是间充质基质细胞（MSC）的成骨分化受损。然而，潜在的分子机制仍然知之甚少。长链非编码RNA（lncRNA）是肿瘤抑制和致癌途径中的重要调控分子。在这里，我们表明，骨髓间充质干细胞表达较少的lncRNA MEG 3相对于那些正常供体在成骨分化。为了评估MEG 3对成骨的影响，制备具有增强或减少的MEG 3的骨髓MSC。我们观察到，MEG 3敲低显著降低了关键成骨标志物的表达，包括Runt相关转录因子2、osterix和骨钙素，而MEG 3过表达增强了它们的表达。此外，MEG 3敲低降低了BMP 4的转录。在这里，我们发现MEG 3对于BMP 4的SOX 2转录抑制至关重要。MEG 3位于BMP 4基因附近，可使转录因子SOX 2与BMP 4启动子分离。含有MEG 3、SOX 2和BMP 4的SOX 2共有位点的稳定复合物表明MEG 3通过直接影响SOX 2活性来激活转录活性。通过使用荧光素酶、染色质免疫沉淀和RNA免疫沉淀等测定，我们发现MEG 3在启动子特异性转录激活机制中具有关键功能。这些结果表明，MEG 3在骨髓间充质干细胞的成骨分化中发挥了重要作用，部分通过激活BMP 4的转录。我们的数据为lncRNA MEG 3表达的生物学和临床意义提供了新的证据，作为识别MM患者的潜在生物标志物和MM中的潜在治疗靶点。干细胞2015;33：1985-1997
Multiple myeloma (MM) is characterized by the impaired osteogenic differentiation of mesenchymal stromal cells (MSCs). However, the underlying molecular mechanisms are still poorly understood. Long noncoding RNAs (lncRNAs) are emerging as important regulatory molecules in tumor‐suppressor and oncogenic pathways. Here we showed that MSCs from MM expressed less lncRNA MEG3 relative to those from normal donors during osteogenic differentiation. To evaluate the effect of MEG3 on osteogenesis, bone marrow MSCs with enhanced or reduced MEG3 were prepared. We observed that MEG3 knockdown significantly reduced the expression of key osteogenic markers, including Runt‐related transcription factor 2, osterix, and osteocalcin, while overexpression of MEG3 enhanced their expression. Additionally, MEG3 knockdown decreased BMP4 transcription. Here we showed that MEG3 was critical for SOX2 transcriptional repression of the BMP4. MEG3, which is located near the BMP4 gene, could dissociate the transcription factor SOX2 from the BMP4 promoter. A stable complex containing the MEG3, SOX2, and the SOX2 consensus site of BMP4 suggested that MEG3 activated transcriptional activity by directly influencing SOX2 activity. By using assays such as luciferase, chromatin immunoprecipitation, and RNA immunoprecipitation, we showed that MEG3 had a critical function in a mechanism of promoter‐specific transcriptional activation. These results suggested that MEG3 played an essential role in osteogenic differentiation in bone marrow MSCs, partly by activating BMP4 transcription. Our data provided novel evidence for the biological and clinical significance of lncRNA MEG3 expression as a potential biomarker for identifying patients with MM and as a potential therapeutic target in MM. Stem Cells 2015;33:1985–1997