SNORD-host RNA Zfas1 is a regulator of mammary development and a potential marker for breast cancer
SNORD-host RNA Zfas1 is a regulator of mammary development and a potential marker for breast cancer
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DOI：
10.1261/rna.2528811
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发表时间：
2011-05-01
期刊：
影响因子：
4.5
通讯作者：
Mattick, John S.
中科院分区：
文献类型：
--
作者：
Askarian-Amiri, Marjan E.;Crawford, Joanna;Mattick, John S.
长非编码RNA(LncRNAs)在发育和疾病中发挥着重要的调控作用。为了确定乳房生物学中的新调控因子，我们鉴定了小鼠乳房发育过程中差异调控的lncRNAs。在表达水平最高和差异最大的基因中，有一个转录本(ZFas1)与蛋白质编码基因Znfx1的第59端反义。在体内，ZFas1 RNA定位于乳腺导管和肺泡内。ZFas1固有地拥有三个先前未描述的C/D盒snoRNAs(SNORD)：Snord12、Snord12b和Snord12c。与非编码SNORD-HOST转录本仅作为产生snoRNAs的载体的普遍假设相反，在乳腺上皮细胞系中敲除ZFas1导致细胞增殖和分化增加，而不显著改变SNORD的水平。为了支持一个独立的功能，我们还发现ZFas1是非常稳定的，半衰期为>；16小时。对SNORD的表达分析表明，这些SNORD在不同的水平上表达，可能是不同结构赋予差异稳定性的结果。虽然ZFas1和它的同线人类直系同源基因ZFAS1之间的一级序列保守性相对较低，但它们预测的二级结构具有相似的特征。与ZFAS1一样，ZFAS1在乳腺中高表达，与正常组织相比，在乳腺肿瘤中表达下调。我们提出了ZFAS1/ZFAS1在调节乳腺肺泡发育和上皮细胞分化中的功能作用，以及它在人类乳腺癌中的失调，表明ZFAS1可能是一个肿瘤抑制基因。
Long noncoding RNAs (lncRNAs) are increasingly recognized to play major regulatory roles in development and disease. To identify novel regulators in breast biology, we identified differentially regulated lncRNAs during mouse mammary development. Among the highest and most differentially expressed was a transcript (Zfas1) antisense to the 59 end of the protein-coding gene Znfx1. In vivo, Zfas1 RNA is localized within the ducts and alveoli of the mammary gland. Zfas1 intronically hosts three previously undescribed C/D box snoRNAs (SNORDs): Snord12, Snord12b, and Snord12c. In contrast to the general assumption that noncoding SNORD-host transcripts function only as vehicles to generate snoRNAs, knockdown of Zfas1 in a mammary epithelial cell line resulted in increased cellular proliferation and differentiation, while not substantially altering the levels of the SNORDs. In support of an independent function, we also found that Zfas1 is extremely stable, with a half-life >16 h. Expression analysis of the SNORDs revealed these were expressed at different levels, likely a result of distinct structures conferring differential stability. While there is relatively low primary sequence conservation between Zfas1 and its syntenic human ortholog ZFAS1, their predicted secondary structures have similar features. Like Zfas1, ZFAS1 is highly expressed in the mammary gland and is down-regulated in breast tumors compared to normal tissue. We propose a functional role for Zfas1/ZFAS1 in the regulation of alveolar development and epithelial cell differentiation in the mammary gland, which, together with its dysregulation in human breast cancer, suggests ZFAS1 as a putative tumor suppressor gene.