Multiple Isoforms of ANRIL in Melanoma Cells: Structural Complexity Suggests Variations in Processing.
Multiple Isoforms of ANRIL in Melanoma Cells: Structural Complexity Suggests Variations in Processing.
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DOI：
10.3390/ijms18071378
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发表时间：
2017-06-27
影响因子：
5.6
通讯作者：
Askarian-Amiri ME
中科院分区：
文献类型：
--
作者：
Sarkar D;Oghabian A;Bodiyabadu PK;Joseph WR;Leung EY;Finlay GJ;Baguley BC;Askarian-Amiri ME
与CDKN2B基因座反义的长非编码RNA ANRIL是从一个包含多种疾病相关多态的基因转录而来的。尽管已鉴定出ANRIL的多种亚型，但已发现某些转录本的表达具有组织特异性，ANRIL转录本的特征仍不完整。已有几种功能与ANRIL相关。在我们看来，对ANRIL功能的研究还为时过早，直到对其丰富的异构体有更全面的认识。我们发现了ANRIL外显子的差异表达，这表明黑色素瘤细胞中存在多种异构体。除了线形异构体，我们还鉴定了环状ANRIL(CircANRIL)。对两个患者来源的转移性黑色素瘤细胞系(NZM7和NZM37)的CircANRIL进一步鉴定表明，存在丰富的环状亚型。此外，在所研究的两个黑色素瘤细胞系中，CircANRIL亚型的补体几乎完全不同。新的外显子也被发现了。我们还发现，线状ANRIL家族在细胞核中丰富，而环状异构体在细胞质中丰富，它们在稳定性上存在明显差异。生物信息学分析表明，内含子内含子黄化节杆菌(Alu)限制性内切酶反向重复序列和外显子跳跃不参与后剪接外显子连接的选择。根据我们的发现，我们假设“ANRIL”在黑色素瘤中具有完全不同的双重功能。这揭示了该基因座的动态性质，并为研究ANRIL在黑色素瘤中的功能奠定了基础。
The long non-coding RNA ANRIL, antisense to the CDKN2B locus, is transcribed from a gene that encompasses multiple disease-associated polymorphisms. Despite the identification of multiple isoforms of ANRIL, expression of certain transcripts has been found to be tissue-specific and the characterisation of ANRIL transcripts remains incomplete. Several functions have been associated with ANRIL. In our judgement, studies on ANRIL functionality are premature pending a more complete appreciation of the profusion of isoforms. We found differential expression of ANRIL exons, which indicates that multiple isoforms exist in melanoma cells. In addition to linear isoforms, we identified circular forms of ANRIL (circANRIL). Further characterisation of circANRIL in two patient-derived metastatic melanoma cell lines (NZM7 and NZM37) revealed the existence of a rich assortment of circular isoforms. Moreover, in the two melanoma cell lines investigated, the complements of circANRIL isoforms were almost completely different. Novel exons were also discovered. We also found the family of linear ANRIL was enriched in the nucleus, whilst the circular isoforms were enriched in the cytoplasm and they differed markedly in stability. With respect to the variable processing of circANRIL species, bioinformatic analysis indicated that intronic Arthrobacter luteus (Alu) restriction endonuclease inverted repeats and exon skipping were not involved in selection of back-spliced exon junctions. Based on our findings, we hypothesise that “ANRIL” has wholly distinct dual sets of functions in melanoma. This reveals the dynamic nature of the locus and constitutes a basis for investigating the functions of ANRIL in melanoma.
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