Identification of linc-NeD125, a novel long non coding RNA that hosts miR-125b-1 and negatively controls proliferation of human neuroblastoma cells

ABSTRACT
The human genome contains some thousands of long non coding RNAs (lncRNAs). Many of these transcripts are presently considered crucial regulators of gene expression and functionally implicated in developmental processes in Eukaryotes. Notably, despite a huge number of lncRNAs are expressed in the Central Nervous System (CNS), only a few of them have been characterized in terms of molecular structure, gene expression regulation and function. In the present study, we identify linc-NeD125 as a novel cytoplasmic, neuronal-induced long intergenic non coding RNA (lincRNA). Linc-NeD125 represents the host gene for miR-125b-1, a microRNA with an established role as negative regulator of human neuroblastoma cell proliferation. Here, we demonstrate that these two overlapping non coding RNAs are coordinately induced during in vitro neuronal differentiation, and that their expression is regulated by different mechanisms. While the production of miR-125b-1 relies on transcriptional regulation, linc-NeD125 is controlled at the post-transcriptional level, through modulation of its stability.
We also demonstrate that linc-NeD125 functions independently of the hosted microRNA, by reducing cell proliferation and activating the antiapoptotic factor BCL-2.

摘要
人类基因组中存在数千种长链非编码RNA（long non-coding RNAs，lncRNAs）。目前认为其中多数转录本是基因表达的关键调控因子，并在真核生物的发育进程中发挥功能性作用。值得关注的是，尽管中枢神经系统（Central Nervous System，CNS）内表达的长链非编码RNA数量众多，但仅有少数被从分子结构、基因表达调控及功能维度完成表征。
本研究将linc-NeD125鉴定为一种新型定位于细胞质、受神经元诱导的基因间长链非编码RNA（long intergenic non-coding RNAs，lincRNA）。linc-NeD125是miR-125b-1的宿主基因，后者是一种已被证实可负向调控人类神经母细胞瘤细胞增殖的微小RNA（microRNA）。
本研究证实，这两种重叠的非编码RNA在体外神经元分化过程中协同诱导表达，且二者的表达受不同机制调控：miR-125b-1的生成依赖转录调控，而linc-NeD125则通过调控自身稳定性在转录后水平受到管控。
此外，本研究还证实，linc-NeD125可不依赖其所寄宿的微小RNA发挥功能，通过抑制细胞增殖并激活抗凋亡因子BCL-2实现其生物学效应。