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European Biopharmaceutical Review

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Recently, evidence has emerged that suggests non-coding RNAs play a distinct role in the transcriptional regulation of gene expression in human cells. Observations from laboratory investigations show that larger forms of antisense non-coding RNAs are functional effector molecules in the transcriptional regulation of endogenous gene expression in human cells. These observations, juxtaposed with recent data that links distinct chromatin signatures with non-coding RNAs, are highly suggestive of a role for the 98 per cent of the human genome that has previously been deemed ‘junk DNA’. This perspective will highlight a few examples of endogenous effector noncoding RNAs that, when disregulated, can result in the progression of a cell to an oncogenic state. We will also discuss the mechanism of action and examples whereby endogenous non-coding RNAs may be regulated by small forms of non-coding RNAs, namely microRNAs.

For several decades, epigenetic changes have been linked to gene expression and, importantly, to oncogenesis. Epigenetics is the study of meiotically and mitotically heritable changes in gene expression which are not coded for in DNA (1). Common types of epigenetic changes include methylation of genomic DNA at CpG sites, as well as methylation of histones. Epigenetic changes can be passed on to daughter cells and, as such, one particular epigenetic incidence can profoundly affect generations of daughter cells. But how epigenetic marks are recruited to particular loci in the genome has remained an enigma. Some clues to epigenetic control of gene expression were obtained from experiments in plants where small non-coding doublestranded RNAs were demonstrated to direct DNA methylation to homology containing loci (2). Similar observations were generated in human cells when small interfering RNAs were designed to target gene promoters (3). Mechanistically, we now know that small non-coding RNAs – either siRNAs or antisense RNAs – can direct the enzymatic machineries for methylation of histone 3 at lysines 9 and 27 (H3K9 and H3K27), and for methylation of DNA to genomic loci containing homology to the particular noncoding RNA (4). While these observations suggested that it is possible to alter gene transcription in a targeted manner, it remained unknown what the effector molecules in human cells were that utilised this RNA directed epigenetic mechanism to control gene expression. Recent developments suggest that the endogenous RNAs actively utilising the RNA directed gene silencing mechanism are antisense non-coding RNAs (5,6).

THE ROLE OF NON-CODING RNAS IN GENE REGULATION

Non-coding RNAs are pervasive throughout the transcriptome of eukaryotes. Long noncoding RNAs appear to be ubiquitously expressed in human cells, and roughly 25 per cent of these non-coding transcripts appear to be antisense to known protein coding genes (7). Non-coding RNAs have been shown to be involved in X inactivation, dosage compensation, imprinting and polycomb mediated silencing (8). It is intriguing, however, that non-coding RNAs do not appear to be universally conserved between various organisms. One observation that may speak to the relative requirement of non-coding RNAs in higher organisms is that the ratio of non-coding DNA increases on an evolutionary scale – a pattern that is not evident in protein coding genomic regions (9). This observation suggests that there is a role for non-coding RNAs in complexity and possibly epigenetic modes of gene regulation. Supporting this notion is the observation that several non-coding RNAs have been found located at, or directly overlapping, 5’ regions of protein coding genes (10). Many of the reported non-coding RNAs that have been detected are in the antisense orientation relative to the transcriptional orientation of the coding gene and have been shown to contain some homology to gene promoter loci (11-14).


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Kevin V Morris is a graduate of Humboldt State University (BS, 1996) and the University of California Davis (PhD, 2001). He was also a postdoctoral fellow at the University of California San Diego and the Beckman Research Institute at the City of Hope before starting his laboratory at the Scripps Research Institute in La Jolla, California. He is currently focusing on determining the role of antisense non-coding RNAs in epigenetic and transcriptional regulation of gene expression in human cells. His particular interest has been in the development of effector RNAs to utilise the endogenous pathways in human cells to transcriptionally silence or activate genes involved in diseases such as HIV-1.

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