Long Non-coding RNA - Long Non-coding RNAs in Disease

Long Non-coding RNAs in Disease

Recent recognition that long ncRNAs function in various aspects of cell biology has focused increasing attention on their potential to contribute towards disease aetiology. A handful of studies have implicated long ncRNAs in a variety of disease states and support an involvement and co-operation in oncogenesis.

While many association studies have identified long ncRNAs that are aberrantly expressed in disease states, we have little understanding of their contribution within disease etiology. Expression analyses that compare tumor cells and normal cells have revealed changes in the expression of ncRNAs in several forms of cancer. For example, in prostate tumours, one of two overexpressed ncRNAs, PCGEM1, is correlated with increased proliferation and colony formation suggesting an involvement in regulating cell growth (Fu 2006). MALAT1 (also known as NEAT2) was originally identified as an abundantly expressed ncRNA that is upregulated during metastasis of early-stage non-small cell lung cancer and its overexpression is an early prognostic marker for poor patient survival rates (Fu 2006). More recently, the highly conserved mouse homologue of MALAT1 was found to be highly expressed in hepatocellular carcinoma (Lin 2007). Intronic antisense ncRNAs with expression correlated to the degree of tumor differentiation in prostate cancer samples have also been reported (Reis 2004). Despite a number of long ncRNAs having aberrant expression in cancer, their function and potential role in tumourogenesis is relatively unknown. For example, the ncRNAs HIS-1 and BIC have been implicated in oncogenesis and growth control, but their function in normal cells is unknown (Eis 2005; Li 1997). In addition to cancer, ncRNAs also exhibit aberrant expression in other disease states. Overexpression of PRINS is associated with psoriasis susceptibility, with PRINS expression being elevated in the uninvolved epidermis of psoriatic patients compared with both psoriatic lesions and healthy epidermis (Sonkoly 2005).

Genome-wide profiling revealed that many transcribed non-coding ultraconserved regions exhibit distinct profiles in various human cancer states (Calin 2007). An analysis of chronic lymphocytic leukaemia, colorectal carcinoma and hepatocellular carcinoma found that all three cancers exhibited aberrant expression profiles for ultraconserved ncRNAs relative to normal cells. Further analysis of one ultraconserved ncRNA suggested it behaved like an oncogene by mitigating apoptosis and subsequently expanding the number of malignant cells in colorectal cancers (Calin 2007). Many of these transcribed ultraconserved sites that exhibit distinct signatures in cancer are found at fragile sites and genomic regions associated with cancer. It seems likely that the aberrant expression of these ultraconserved ncRNAs within malignant processes results from important functions they fulfil in normal human development.

Recently, a number of association studies examining single nucleotide polymorphisms (SNPs) associated with disease states have been mapped to long ncRNAs. For example, SNPs that identified a susceptibility locus for myocardial infarction mapped to a long ncRNA, MIAT (myocardial infarction associated transcript) (Ishii 2006). Likewise, genome-wide association studies identified a region associated with coronary artery disease (McPherson 2007) that encompassed a long ncRNA, ANRIL (Pasmant 2007). ANRIL is expressed in tissues and cell types affected by atherosclerosis (Broadbend 2008, Jarinova 2009) and its altered expression is associated with a high-risk haplotype for coronary artery disease (Jarinova 2009, Liu 2009)

The complexity of the transcriptome, and our evolving understanding of its structure may inform a reinterpretation of the functional basis for many natural polymorphisms associated with disease states. Many SNPs associated with certain disease conditions are found within non-coding regions and the complex networks of non-coding transcription within these regions make it particularly difficult to elucidate the functional effects of polymorphisms. For example, a SNP both within the truncated form of ZFAT and the promoter of an antisense transcript increases the expression of ZFAT not through increasing the mRNA stability, but rather by repressing the expression of the antisense transcript (Shirasawa 2004).

The ability of long ncRNAs to regulate associated protein-coding genes may contribute to disease if misexpression of a long ncRNA deregulates a protein coding gene with clinical significance. In similar manner, an antisense long ncRNA that regulates the expression of the sense BACE1 gene, a crucial enzyme in Alzheimer’s disease etiology, exhibits elevated expression in several regions of the brain in individuals with Alzheimer's disease (Faghihi 2008). Alteration of the expression of ncRNAs may also mediate changes at an epigenetic level to affect gene expression and contribute to disease aetiology. For example, the induction of an antisense transcript by a genetic mutation led to DNA methylation and silencing of sense genes, causing β-thalassemia in a patient (Tufarelli 2003).