The RNA World Hypothesis suggests that prebiotic life revolved around RNA instead of DNA and proteins. Many discoveries such as housekeeping RNAs (rRNA, tRNA, etc.) supported the messenger RNA (mRNA) model that is the pillar of the central dogma of molecular biology, which was first devised in the late 1950s. Thirty years later, the first regulatory non-coding RNAs (ncRNAs) were initially identified in bacteria and then in most eukaryotic organisms. A few long ncRNAs (lncRNAs) such as H19 and Xist were characterized in the pre-genomic era but remained exceptions until the early 2000s. Indeed, when the sequence of the human genome was published in 2001, studies showed that only about 1.2% encodes proteins, the rest being deemed "non-coding." It was later shown that the genome is pervasively transcribed into many ncRNAs, but their functionality remained controversial. Since then, regulatory lncRNAs have been characterized in many species and were shown to be involved in processes such as development and pathologies, revealing a new layer of regulation in eukaryotic cells. This newly found focus on lncRNAs, together with the advent of high-throughput sequencing, have led to the rapid discovery of many novel transcripts which were further characterized and classified according to specific transcript traits. LncRNAs are certainly revolutionizing the field of molecular biology, inching towards playing a part in RNA therapeutics. Targeting lncRNAs is quite difficult because of their large size and heterogeneous mode of action, which may explain why their evaluation is not as advanced as that of miRNAs. Nevertheless, they have significant potential as future therapeutic targets.
So, What Exactly are the Long Non-Coding RNAs?
Long non-coding RNAs or lncRNAs are RNAs over 200 nucleotides long that are not translated into proteins. They are found in different places within the cell, including chromatin, nucleus, cytoplasm, and exosomes. Most of them (78%) are tissue-specific, compared to just 19% for mRNAs. Also, their abundance in cells is ~10 fold lower than mRNAs. In 2018, a comprehensive integration of exiting databases and published literature placed their number at 2,70,044 in humans.
Functions of Long Non-Coding RNAs
LncRNAs can originate from the locus that they regulate, usually from the antisense strand, and regulate their target in cis (Natural antisense Transcripts (NATs), or they can map to entirely different genomic regions form their targets (introns, pseudogenes, and non-coding DNA) and cause regulation in trans. They can also be associated with promoters, enhancers or other regulatory regions and do not have a homogeneous mode of action. They can activate or repress their targets and can work by a number of mechanisms. Their functions may be categorized based on their location with respect to the cell (nucleus, cytoplasm, or exosome), the molecular pathways they are part of, or the pathophysiological processes they have roles in.
LncRNAs function as parts of various processes in cells or tissues in multiple ways–
• Post transcriptional modification, like splicing
• Post translational regulation
Besides, lncRNAs play diverse roles in physiological processes, like aging and disease.
• Aging: Aging-associated lncRNAs are highly tissue-specific but are expressed with a common pool of protein coding genes and are associated with similar functional categories. Aging-associated lncRNAs are associated with immune system processes as well as with signal transduction, transcription, and translation.
• Disease: Recent research has implicated lncRNAs in a range of diseases, starting from different cancers to neurological, cardiovascular, and other disorders.
Cancer: LncRNAs demonstrably play roles in the incidence of various cancers like lung cancer, breast cancer, leukemia, carcinomas, epithelial cancer, gastrointestinal stromal tumors and others (shown in the image below). Currently, cancer therapy is greatly hampered by many difficulties, e.g., specific targeting of cancer cells without interfering with normal tissue function, specific delivery of antitumor drugs, and, in case of carcinoma of unknown primary, exact characterization of the malignancy. Here, long ncRNAs could offer a number of advantages, both as diagnostic and prognostic markers but also as novel specific therapeutic targets. The latter, of course, first requires detailed knowledge about the tumor-specific ncRNA function and its requirement for essential cancer cell properties.
Neurological disease: The dysregulation of lncRNAs could result in neurological diseases like schizophrenia, autism spectrum disorder, Parkinson’s, Huntington’s and Alzheimer’s diseases. This can be brought about by a variety of mechanisms.
Cardiovascular disease: LncRNAs play various roles in cardiac afflictions like cardiac hypertrophy and myocardial infarction.
Other disorders: LncRNAs also play critical roles in the development of many other disorders like obesity, diabetes, depression, asthma, muscular dystrophy, psoriasis, fragile X syndrome, etc. A study has even found its role in antiviral innate responses
Thus, the budding field of the once-called “junk” matter continues to throw new surprises to us at an astonishing pace. Their promise as biomarkers and therapeutics certainly makes the upcoming days very exciting.