Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Bulfinch 457, Boston, Massachusetts 02114, USA.
J Mol Endocrinol. 2012 Apr 2;48(3):R45-53. doi: 10.1530/JME-12-0008. Print 2012 Jun.
Maternally expressed gene 3 (MEG3) is an imprinted gene belonging to the imprinted DLK1-MEG3 locus located at chromosome 14q32.3 in humans. Its mouse ortholog, Meg3, also known as gene trap locus 2 (Gtl2), is located at distal chromosome 12. The MEG3 gene encodes a long noncoding RNA (lncRNA) and is expressed in many normal tissues. MEG3 gene expression is lost in an expanding list of primary human tumors and tumor cell lines. Multiple mechanisms contribute to the loss of MEG3 expression in tumors, including gene deletion, promoter hypermethylation, and hypermethylation of the intergenic differentially methylated region. Re-expression of MEG3 inhibits tumor cell proliferation in culture and colony formation in soft agar. This growth inhibition is partly the result of apoptosis induced by MEG3. MEG3 induces accumulation of p53 (TP53) protein, stimulates transcription from a p53-dependent promoter, and selectively regulates p53 target gene expression. Maternal deletion of the Meg3 gene in mice results in skeletal muscle defects and perinatal death. Inactivation of Meg3 leads to a significant increase in expression of angiogenesis-promoting genes and microvessel formation in the brain. These lines of evidence strongly suggest that MEG3 functions as a novel lncRNA tumor suppressor.
母系表达基因 3（MEG3）是一个印迹基因，属于印迹的 DLK1-MEG3 基因座，位于人类 14q32.3 染色体上。其小鼠同源物 Meg3，也称为基因捕获位点 2（Gtl2），位于染色体 12 的远端。MEG3 基因编码一个长非编码 RNA（lncRNA），并在许多正常组织中表达。MEG3 基因的表达在不断扩大的原发性人类肿瘤和肿瘤细胞系中丢失。多种机制导致肿瘤中 MEG3 表达的丢失，包括基因缺失、启动子 hypermethylation 和基因间差异甲基化区域的 hypermethylation。MEG3 的重新表达抑制了培养中的肿瘤细胞增殖和软琼脂中的集落形成。这种生长抑制部分是由 MEG3 诱导的细胞凋亡引起的。MEG3 诱导 p53（TP53）蛋白的积累，刺激 p53 依赖性启动子的转录，并选择性调节 p53 靶基因的表达。母系 Meg3 基因缺失导致小鼠骨骼肌缺陷和围产期死亡。Meg3 的失活导致促进血管生成基因的表达显著增加，并导致大脑中小血管的形成。这些证据强烈表明 MEG3 作为一种新型的 lncRNA 肿瘤抑制因子发挥作用。
