MicroRNAs (miRNAs) are short (22 nucleotides,more or less) single-stranded RNA molecules which do not encode proteins. Discovered in 1993 they are recently coming under intense research scrutiny because of the important roles they play in post-transcriptional regulation of gene expression. According to a feature article published last year in Gen Tapping miRNA-Regulated Pathways, “miRNAs are master regulators of gene expression, according to William S. Marshall, Ph.D., president and CEO of miRagen Therapeutics. “You can have one microRNA that controls multiple genes and one gene that is controlled by multiple microRNAs.” They exert negative regulation and have been shown to control expression of entire signaling pathways(ref).” “About 3% of human genes encode for miRNAs, and up to 30% of human protein coding genes may be regulated by miRNAs. MicroRNAs play a key role in diverse biological processes, including development, cell proliferation, ifferentiation, and apoptosis(ref).”
The number of discovered human miRNAs continues to grow. “ – It can be argued that, based on computational analysis “there may be as many as 50,000 miRNAs in the human genome and each may have as many as a few thousand potential targets(ref).” “Approximately 400 to 500 miRNAs have been characterized in humans to date, according to Dr. Marshall, and 80–150 are typically expressed in any particular cell type(ref).” That was written some 18 months ago. I suspect that by now the number of characterized miRNAs is climbing up over a thousand.
MicroRNAs work by turning gene expression off. “MicroRNAs downregulate gene expression either by degradation of messenger RNA through the RNA interference pathway or by inhibiting protein translation(ref).” “–more short regulatory RNAs were identified in almost all multicellular organisms, including flowering plants, worms, flies, fish, frogs, mammals [38, 40, 41, 48, 71], and in single cellular algae and DNA viruses [66, 75]. — Computational predictions of miRNA targets suggest that up to 30% of human protein coding genes may be regulated by miRNAs [46, 68]. This makes miRNAs one of the most abundant classes of regulatory genes in humans. MicroRNAs are now perceived as a key layer of post-transcriptional control within the networks of gene regulation(ref).”
MicroRNAs play many roles in organisms “The literature includes examples of miRNAs that function as oncogenes, with their overexpression contributing to tumorigenesis, and of others that act as tumor suppressors, which when downregulated contribute to cancer(ref).” A single miRNA may simultaneously impact in complicated ways on several different genes and gene-activation pathways. “There is accumulating evidence that short RNAs can not only affect the levels of proteins, but that proteins may also affect the production of microRNAs(ref).”
Large complements of miRNAs are expressed in embryonic stem cells as pointed out in the publication MicroRNA discovery and profiling in human embryonic stem cells by deep sequencing of small RNA libraries. “A custom data analysis pipeline delineated expression profiles for 191 previously annotated miRNAs, 13 novel miRNAs, and 56 candidate miRNAs.” Further, interestingly, some of the miRNAs found in embryonic stem cells seem not to be found in other cells and seem to be regulated by many of the same transcription factors used to revert somatic cells back to induced pluripotent stem status “Finally, integration of our data with genome-wide chromatin immunoprecipitation data on OCT4, SOX2, and NANOG binding sites implicates these transcription factors in the regulation of nine of the novel/candidate miRNAs identified here(ref).” miRNAs in embryonic stem cells seem to play important roles in cell differentiation.
Another study MicroRNA expression patterns and function in endodermal differentiation of human embryonic stem cells concludes “Our results demonstrate that expression of specific miRNAs correlates with that of specific genes upon differentiation, and highlight the potential role of miRNAs in endodermal differentiation of hESC.”
Dozens of new papers related to miRNAs have been published in the last few months, and the perceived regulatory importance of these little critters continues to grow. “Thousands of miRNA genes have been found in diverse species, and many of them are highly conserved. With the miRNA roles identified in nearly all aspects of biological processes, evidence is mounting that miRNAs could represent a new layer of regulatory network, and their regulatory effect might be much more pervasive than previously suspected(ref).”A number of the more-recent publications have focused on the roles of miRNAs in cancers(ref)(ref)(ref), in Alzheimer’s disease(ref)(ref), in herpes infections(ref), in coronary artery cell senescence(ref) and restenosis(ref) and in many other disease processes. Examples of efforts by university research scientists and biotech companies to develop therapeutic products based on miRNA approaches are outlined in the Gen article.
Of special interest to me is yet-another view of aging in which miRNAs play the lead roles. Quoting again from the Gen article, “Eugenia Wang, Ph.D., professor at the University of Louisville, has proposed that miRNAs have a critical role in “a universal or system-specific programmatic shift of signaling control” that occurs at mid-life and brings about a decline in cellular health status associated with aging, which may precipitate increased risk of late-life diseases. In her presentation, she will review the hypothesis that the changes in expression of most if not all aging-related genes are controlled by underlying hubs and the belief that miRNAs, acting as molecular master switches, are candidate hubs.”
In fact the May 2009 issue of Current Genomics focuses on the roles of miRNAs in the aging process and Dr. Wang wrote the editorial Hot Topic: MicroRNA Regulation and its Biological Significance in Personalized Medicine and Aging. “This issue focuses on a discussion of microRNA’s post-transcriptional control of the aging process.” The ground covered in that issue is large and interesting enough for me to make it the subject of a subsequent post. For the moment I will comment that Dr. Wang’s view of aging appears to suggest specific mechanisms for the operation of the 13th theory of aging covered in my treatise, Programmed Epigenomic Changes. As I understand it, this view says that miRNAs are the signaling messengers and “hit men” for programmed aging, progressively and systematically switching off disease-protecting genes as an organism ages.
It is interesting that in the previous post Homicide by DNA methylation I outlined a view of a Russian scientist suggesting a different mechanism for operation of the Programmed Epigenomic Changes theory. This view suggests that mutated genes due to progressive DNA methylation might be the cause for genomic and therefore somatic deterioration and loss of disease protection with age. Of course, both the miRNA explanation and the DNA methylation explanations for aging could be compatible, and molecular links between the two sets of process could be discovered. I plan to come back to this topic.