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Regulatory RNA
The earliest known regulators of gene expression were proteins known as repressors and activators, regulators with specific short binding sites within enhancer regions near the genes to be regulated in their expression.[1] More recently, RNAs have been found to regulate genes as well. There are several different kinds of RNA-dependent processes in eukaryotes regulating the expression of genes at various points, such as RNAi repressing genes post-transcriptionally, long non-coding RNAs shutting down blocks of chromatin epigenetically, and enhancer RNAs inducing increased gene expression.[2] In addition to these mechanisms in eukaryotes, both bacteria and Archaea have been found to use regulatory RNAs extensively. Bacterial small RNA and the CRISPR system are examples of such prokaryotic regulatory RNA systems.[3] Fire and Mello who discovered RNA interference by micro RNAs (miRNAs), specific short RNA molecules that can base-pair with messenger RNAs (mRNAs), were awarded the 2006 Nobel Prize in Physiology or Medicine.[4]
RNA Interference by miRNAs
Post-transcriptional expression levels of many genes can be controlled by RNA interference, in which miRNAs, specific short RNA molecules, pair with messenger RNA regions and target the mRNAs for degradation.[5] This antisense based process involves steps that first process the RNA so that it can base-pair with a region of its target messenger RNAs (mRNAs). Once the base pairing occurs, other specific proteins conduct the mRNA to be destroyed by nucleases.[2] Fire and Mello who discovered RNA interference were awarded the 2006 Nobel Prize in Physiology or Medicine.[4]
Long Noncoding RNAs
Next to be linked to regulation were Xist and other long noncoding RNAs associated with X chromosome inactivation. Their roles, at first mysterious, were shown by Jeannie T. Lee and others to be the silencing of blocks of chromatin via recruitment of Polycomb complex so that messenger RNA could not transcribed from them.[6] Additional lncRNAs, currently defined as RNAs of more than 200 base pairs that do not appear to have coding potential,[7] have been found associated with regulation of stem cell pluripotency and cell division.[7]
Enhancer RNAs
The third major group of regulatory RNAs is called enhancer RNAs.[7] It is not clear at present whether or not they are a unique category of RNAs of various lengths or they constitute a distinct subset of lncRNAs. In any case, they are transcribed from enhancers, which are known regulatory sites in the DNA near genes they regulate.[7][8] They up-regulate the transcription of the gene(s) under control of the enhancer from which they are transcribed.[7][9]
Regulatory RNA in bacteria and Archaea
At first, regulatory RNA was thought to be a eukaryotic phenomenon, a part of the explanation for why so much more transcription was seen than was predicted in higher organisms. But as soon as researchers began to look for possible RNA regulators in bacteria, they turned up there as well.[3] Currently, the ubiquitous nature of systems of RNA regulation of genes has been discussed as support for the RNA World theory.[2][10] Bacterial small RNAs generally act via antisense pairing with mRNA to down regulate its translation either by affecting stability or affecting cis-binding ability. [2] Riboswitches have also been discovered. They are cis-acting regulatory RNA sequences acting allosterically. They change shape when they bind metabolites so that they gain or lose the ability to bind chromatin in order to regulate expression of genes.[11][12] Archae have systems of regulatory RNA as well as bacteria.[13] The CRISPR system recently being used to edit DNA in situ acts via regulatory RNAs in Archaea and bacteria to provide protection against virus invaders.[2][14]
References
- F Jacob and J Monod (1961) "Genetic Regulatory Mechanisms in the Synthesis of Proteins. Journal of Molecular Biology 3: 318-356.
- Kevin Morris and John Mattick. (2014) “The rise of regulatory RNA” Nature Reviews Genetics15:423-437.
- S. Gottesman (2005) “Micros for microbes: non-coding regulatory RNAs in bacteria.” Trends in Genetics 21,399–404.
- 1 "The Nobel Prize in Physiology or Medicine 2006". Nobelprize.org. Nobel Media AB 2014. Web. 6 Aug 2018. <http://www.nobelprize.org/nobel_prizes/medicine/laureates/2006/>
- Fire et al. 1998 “Potent and Specific Genetic Interference by double stranded RNA in Ceanorhabditis elegans” Nature 391:806-811.
- J Zhao, BK Sun, JA Erwin, JJ Song, and JT Lee. (2008) “Polycomb proteins targeted by a short repeat RNA to the mouse X chromosome.” Science 322:750–6. [PubMed: 18974356],
- John L. Rinn and Howard Y. Chang. (2012) “Genome regulation by long noncoding RNAs” Ann. Rev. Biochem 81:1-25. doi: 10.1146/annurev-biochem-051410-092902
- RJ Taft, CD Kaplan., C Simons, and JS Mattick, (2009). Evolution, biogenesis and function of promoter- associated RNAs. Cell Cycle 8, 2332–2338.
- UA Orom, T Derrien, M Beringer, K Gumireddy, A. Gardini, et al.(2010) ‘Long noncoding RNAs with enhancer-like function in human cells.” Cell 143:46–58. [PubMed: 20887892]
- J. W. Nelson, R. R. Breaker (2017) "The lost language of the RNA World."Sci. Signal.10,eaam8812 1-11.
- WC Winklef. (2005) “Riboswitches and the role of noncoding RNAs in bacterial metabolic control. “Curr. Opin. Chem. Biol. 9, 594–602.
- BJ Tucker and RR Breaker (2005). “Riboswitches as versatile gene control elements.”Curr. Opin. Struct. Biol. 15, 342–348.
- FJ Mojica, C Diez-Villasenor, E Soria, and G Juez, (2000) “Biological significance of a family of regularly spaced repeats in the genomes of archaea, bacteria and mitochondria.”Mol. Microbiol. 36, 244–246.
- S Brouns, MM Jore, M Lundgren, E Westra, R Slijkhuis, A Snijders, M Dickman, K. Makarova, E. Koonin, J Van Der Oost. (2008) “Small CRISPR RNAs guide antiviral defense in prokaryotes” Science 321, 960–964. doi: 10.1126/science.1159689.