CHALLENGES OF NON-CODING RNAs IN DISEASES

A non-coding Ribonucleic acid or non-coding RNA (nc RNA) is a functional RNA molecule that is not translated into a protein. Less-frequently used synonyms are non-protein-coding RNA (npcRNA), non-messenger RNA (nmRNA) and functional RNA (fRNA). The DNA sequence from which a non-coding RNA is transcribed is often called an RNA gene. Non-coding RNA genes include highly abundant and functionally important RNAs such as transfer RNAs (tRNAs) and ribosomal RNAs (rRNAs), as well as RNAs such as small nucleolar RNAs (snoRNAs), microRNAs, small interfering RNAs (siRNAs), exRNAs, and piwi-interacting RNAs (piRNAs ) and the long ncRNAs (Fig.1). The number of ncRNAs encoded within the human genome is unknown, however recent transcriptomic and bioinformatics studies suggest the existence of thousands of ncRNAs. Since many of the newly identified ncRNAs have not been validated for their function, it is possible that many are non-functional.
Many classes of non-coding RNA have been described that are associated with the transcriptional start sites (TSSs) of genes: for e xa mple, promoter-associated small RNAs (PASRs), TSS-associated RNAs (TSSa-RNAs), promoter upstream transcripts (PROMPTs) and transcription init iation RNAs (tiRNAs). For all of these classes, their biological functions are poorly defined, although they are probably involved in transcription regulation. Finally, a specialized type of lncRNA, known as telomeric repeat-containing RNAs (TERRAs), is transcribed from telomeres. TERRAs help to maintain the integrity of telomeric heterochromatin by regulating telomerase activity



Figure 1. Classes of non-coding RNAs.

Non-coding RNAs make up the majority of transcribed RNA and have a wide range of functions in cellu lar and developmental processes. Consequently, they are also implicated in the development and pathophysiology of many diseases and represent potential targets for therapeutic intervention. Different types of non-coding RNA have been implicated in non-neoplastic disease (Table 1).
For e xa mple, in Alzheimer's disease, a conserved non-coding antisense transcript drives rapid feed-forward regulation of BACE1(β-secretase1). In addition, enrichment for T-UCR (transcribed ultraconserved region) loci is seen in chromosomally imbalanced regions that are associated with pathology in neurodevelopmental disorders. snoRNAs have been found to have an important role in imprinting disorders, specifically those with a neurodevelopmental component such as Prader–Willi syndrome (PWS) and Angelman syndrome. These disorders are caused by several genetic and epigenetic mechanis ms involving the 15q11–q13 imprinted locus in chromosome, which contains a cluster of tandemly arranged snoRNAs.

                                                                                                                           Table 1
Non-coding RNAs in non-tumoral disorders ( by Esteller M., 2011)

BACE1 –β-secretase1; CDKN2A – cyclin-dependent kinase inhibitor 2A; HYMAI – hydatidiform mole associated and imprinted; ICF syndrome – immunodeficiency, centromeric region instability and facial anomalies syndrome; KCNQ1OT1 - KCNQ1 opposite strand/antisense transcript 1; NESP – also known as GNAS; NESP-AS - NESP antisense; T-UCR - t ranscribed ultraconserved region.

In mammals, conditional ablation of essential components of the miRNA machinery, such as Dicer, suggests that miRNAs are crucial for brain function. For instance, the importance of miRNAs for terminal differentiation and the maintenance of many neuronal types has been demonstrated. Disruption of miRNA processing has been shown to cause hallmarks of: ataxia in Purkinje cells; multiple sclerosis in oligodendrocyte cells; Parkinson's disease in dopaminergic cells; and Alzheimer's disease in α-calcium/calmodulin-dependent protein kinase type II (α CaMKII)-expressing neurons.
Several monogenic disorders have been found to have aberrant miRNA e xpression profiles in tissue types that are relevant to the pathophysiology of the disease, and this list is rapidly increasing. In addition, specific miRNA defects have been shown to underlie particular diseases; for exa mple, miR-145 and miR-146a deletions are involved in the 5q syndrome phenotype. As well as genetic mutations that underlie miRNA dysfunction in inherited disease, we should also consider those diseases in which alterations of epigenetic marks cause misregulation of non -coding RNA e xp ression. Recent disease studies have found disrupted exp ression of miRNAs that are transcribed from Cp G island s, at which the e xpression of the miRNA is regulated by DNA methyltransferases (DNMTs). This situation occurs in immunodeficiency, centromere instability and facial anomalies (ICF) syndrome, in which patients harbour mutations in the gene that encodes DNMT 3B, and in Rett's syndrome, wherein mutations in the methyl CpG-binding protein 2 (MECP2) gene are responsible. Dysregulation of miRNAs in ICF syndrome has also been associated with an aberrant histone modification profile.
The roles of non-coding RNAs in tumorogenesis have most thoroughly been studied with respect to miRNAs and to transcribed ultraconserved regions (T-UCRs) (Table 2). In human cancer, miRNA e xpression profiles differ between normal tissues and the tumors that are derived from them and differ between tumor types. miRNAs can act as oncogenes or as tumor suppressors and can have key functions in tumorogenesis. Dysregulation of miRNAs in cancer can occur through epigenetic changes (for e xa mple, promoter Cp G island hypermethylation in the ca se of the miR-200 family) and genetic alterations, which can affect the production of the primary miRNA transcript, their processing to mature miRNAs and/or interactions with mRNA targets. From a genetic standpoint, one of the first associations to be obse rved between miRNAs and cancer development was miR-15 and miR-16 dysregulation in most B cell chronic lymphocytic leukemia as a result of chromosome 13q14 deletion. Interestingly, miRNAs are frequently located in fragile regions of the chromosomes that are involved in ovarian and breast carcinomas and melanomas.
                                                                                                                               Table 2

Non-coding RNAs disrupted by either genetic or epigenetic means in cancer ( by Esteller M., 2011)

BCL2 - B cell CLL/ lymphoma 2; BIM, also known as BCL2L11; CDC42 - cell-division cycle 42; CDK6 - cyclin- dependent kinase 6; EMT - epithelial-to-mesenchymal transition; T-UCR, transcribed ultraconserved region.

From what has been compiled, the deregulation of biogenesis and functional roles of non-coding RNAs were, as e xpected at the crossroads of different human pathologies ranging from cancer to neurodegenerative and immune diseases.
Specifically in relation to disease, understanding the precise roles of non-coding RNAs, particularly non-miRNAs, is a key challenge. Non-coding RNAs, such as PIWI-interacting RNAs (piRNAs), s mall nucleolar RNAs (snoRNAs), transcribed ultraconserved regions (T-UCRs) and large intergenic non-coding RNAs (linc RNAs) are emerging as key elements of cellu lar homeostasis.
Finally the continued understanding of the molecular mechanisms and signaling pathways where non -coding RNAs participate should offer new insights to define new diagnostic strategies and open new avenues for therapies .

References

1. Esteller M. Non-coding RNAs in human disease. Nature Reviews Genetics. 2011; 12, P. 861-874.
2. Go mes A.Q. , Nolasco S., and Soares H. Non-Coding RNAs: Multi-Tasking Molecules in the Cell Journal Molecular Sciences. 2013; 14, P. 16010-16039.
3. Troy A. and Sharpless N.E. Genetic ―lnc‖-age of noncoding RNAs to human disease. Journal Clinical. Invest. 2012; 122(11): P. 3837–3840.