Programa de Recerca en Càncer, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain.
Kimmel Center for Biology and Medicine at the Skirball Institute, Department of Pathology, New York University School of Medicine, New York University, USA.
Nucleic Acids Res. 2018 Jan 9;46(1):146-158. doi: 10.1093/nar/gkx958.
Besides controlling epithelial-to-mesenchymal transition (EMT) and cell invasion, the Snail1 transcriptional factor also provides cells with cancer stem cell features. Since telomere maintenance is essential for stemness, we have examined the control of telomere integrity by Snail1. Fluorescence in situ hybridization (FISH) analysis indicates that Snail1-depleted mouse mesenchymal stem cells (MSC) have both a dramatic increase of telomere alterations and shorter telomeres. Remarkably, Snail1-deficient MSC present higher levels of both telomerase activity and the long non-coding RNA called telomeric repeat-containing RNA (TERRA), an RNA that controls telomere integrity. Accordingly, Snail1 expression downregulates expression of the telomerase gene (TERT) as well as of TERRA 2q, 11q and 18q. TERRA and TERT are transiently downregulated during TGFβ-induced EMT in NMuMG cells, correlating with Snail1 expression. Global transcriptome analysis indicates that ectopic expression of TERRA affects the transcription of some genes induced during EMT, such as fibronectin, whereas that of TERT does not modify those genes. We propose that Snail1 repression of TERRA is required not only for telomere maintenance but also for the expression of a subset of mesenchymal genes.
除了控制上皮-间充质转化 (EMT) 和细胞侵袭外，Snail1 转录因子还赋予细胞癌症干细胞特征。由于端粒维持对于干细胞特性至关重要，我们研究了 Snail1 对端粒完整性的控制。荧光原位杂交 (FISH) 分析表明，Snail1 耗尽的小鼠间充质干细胞 (MSC) 既有明显增加的端粒改变，也有较短的端粒。值得注意的是，Snail1 缺陷型 MSC 具有更高水平的端粒酶活性和长非编码 RNA 称为端粒重复 RNA (TERRA)，TERRA 是一种控制端粒完整性的 RNA。因此，Snail1 的表达下调端粒酶基因 (TERT) 和 TERRA 2q、11q 和 18q 的表达。TERRA 和 TERT 在 TGFβ诱导的 NMuMG 细胞 EMT 中瞬时下调，与 Snail1 表达相关。全转录组分析表明，TERRA 的异位表达会影响 EMT 过程中诱导的某些基因的转录，如纤连蛋白，而 TERT 的表达则不会改变这些基因。我们提出，Snail1 对 TERRA 的抑制不仅是端粒维持所必需的，而且是表达一组间充质基因所必需的。
