MORT (long Non-coding RNA)

''MORT'' (Mortal Obligate RNA Transcript (also known as ''ZNF667-AS1'')) is a long non-coding RNA (lncRNA) of the intergenic type ( lincRNA) that is specific to humans and great apes. The ''MORT'' transcript is produced in all mortal cell types, but is lost in a large fraction of the most common human cancers and therefore might have a tumor suppressive function.

Genomic location

The ''MORT'' gene is located on human chromosome 19, at position 56,989,000–57,007,000 ( hg19) within a cluster of zinc finger genes (ZNF genes). The ''MORT'' gene consists of 2 exons, 260 and 1270 bp, respectively, that are separated by a 16 kbp intron. A large portion of the second ''MORT'' exon is formed by repetitive elements – two LINEs and an LTR element.
The ''MORT'' promoter is located in a CpG island that is shared with the ''ZNF667'' gene; the two genes reside in a head to head orientation with one another. Despite the ''MORT'' gene's location inside a cluster of ZNF genes, the ''MORT'' gene is not homologous to any ZNF genes. While the ''MORT'' gene is in a head to head orientation with ''ZNF667'', ''MORT'' does not overlap the ''ZNF667'' gene, nor does it share any antisense homology to ''ZNF667'', so the officially used symbol ''ZNF667-AS1'' is somewhat misleading.

Evolution

''MORT'' has orthologs only in great apes – chimpanzees, gorillas and orangutans, and the RNA expression data indicates that the ''MORT'' transcript is expressed in these species. Thus, from a phylogenetic point view, ''MORT'' is likely a young lincRNA gene that emerged during evolution of great apes. It is possible that the long life span of the great apes required evolution of additional genes with tumor suppressive activity, and that ''MORT'' is such an example.

Silencing in cancer

''MORT'' is expressed in all 16 normal human tissues reported in the Illumina body map data, as well as all ''in vitro'' cultured, finite lifespan, human cell strains that have been analyzed. In contrast, ''MORT'' gene expression is lost in a large percentage of human cancers and human cancer cell lines. Using data from human cancers curated in TCGA, ''MORT'' RNA expression and DNA methylation state were evaluated in the 10 most common male cancers and the 10 most common female cancers (totalling 17 different cancer types based on TCGA classification). Analysis shows that the ''MORT'' gene expression is silenced by DNA hypermethylation of its CpG island promoter in a majority of human tumor samples in 15 of these 17 human cancers.

The 15 tumor types where ''MORT'' is frequently silenced are acute myeloid leukemia, bladder urothelial carcinoma, breast invasive carcinoma, colon adenocarcinoma, head and neck squamous-cell carcinoma, kidney renal clear cell carcinoma, kidney renal papillary cell carcinoma, liver hepatocellular carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, lymphoid neoplasm diffuse large B-cell lymphoma, pancreatic adenocarcinoma, rectum adenocarcinoma, skin cutaneous melanoma, and Uterine Corpus Endometrial Carcinoma. MORT is silenced in cervical cancer and therefore may serve as an independent prognostic factor with low MORT expression be associated with a decreased overall survival.

Since cell immortality is an obligate feature of the cancer cell and ''MORT'' was discovered as a target of epigenetic silencing at the boundary where finite lifespan human cells transition from mortal to immortal, ''MORT’s'' epigenetic inactivation may create a cellular state permissive to cell immortalization and suggests a possible tumor suppressive mechanism of ''MORT''’s action. If this prediction is true, then epigenetic silencing of ''MORT'' should be an early identifiable lesion during human carcinogenesis and predicted to occur in premalignant lesions where cells have acquired pathologic immortality on their route to malignant transformation. Indeed, recent work has shown that ''MORT'' is epigenetically silenced in both DCIS, a premalignant lesion of invasive breast cancer, and colonic adenomas, a premalignant lesion of colon adenocarcinoma. Furthermore epigenetic silencing of ''MORT'' is associated with luminal, hormone receptor positive breast cancer, overexpression of the oncogene ''CCND1'', and ''GATA3'' mutations, but is negatively correlated with ''p53'' mutations. In summary, aberrant DNA hypermethylation-mediated epigenetic silencing of ''MORT'' occurs early during human carcinogenesis apparently coincident with when a mortal cell pathologically transitions to an immortal cell.

Cellular Function

The precise molecular function of ''MORT'' remains enigmatic; however, it is known that ''MORT'' is found preferentially in the cell cytoplasm with differential density centrifugation showing that ''MORT'' is enriched in the 100,000 g fraction, which contains polysomes, microsomes, endoplasmic reticulum, and the plasma membrane. Evidence is mounting that ''MORT'' acts as a regulator of protein translation through interactions with RNA binding proteins.

References

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Genes
Genes on human chromosome 19
Non-coding RNA
Epigenetics
Cancer epigenetics