Debunking myths on genetics and DNA

Thursday, July 5, 2012

Viruses and epigenetics: old tricks, new findings

Different cells express different genes. Which genes are expressed and which, instead, are silenced, is regulated either at the transcriptional or at the post-transcriptional level. In an older post I described how DNA is arranged inside the nucleus and how changes in chromatin (the "yarn" of DNA and other proteins like histone complexes) can affect gene expression. Transcriptional gene regulation happens at the chromatin level, in other words, genes are expressed or silenced due to rearrangements of the DNA inside the nucleus.

Post-transcriptional regulation happens at the messenger RNA level: mature single-stranded mRNAs are created from primary gene transcript in order to make proteins. However, if this mRNA is either destroyed or bound to a complementary RNA strand, it can no longer make the protein and the gene is effectively silenced. These bits of RNAs are called RNA interference (RNAi) and most of them are endogenous to the cell, like the ~1,000 micro RNAs (miRNAs) encoded by our genome.
"In silico analyses based on complementarity of miRNAs and their putative mRNA targets have led to estimates that miRNAs may regulate up to 30% of protein-coding human mRNAs. Not surprisingly, early analyses of the more than 1,000 human miRNA sequences aligned against a large dataset of pathogenic mammalian viral genomes indicated that most, if not all, viruses are recognized by one or more cellular miRNAs [1]."
What this means is that endogenous miRNAs are able to mediate viral infections. For example, studies have shown that liver-specific miRNAs can aid hepatitis C replication, while others repress the hepatitis B virus.
"Taken together, the accumulated findings support the concept that ambient miRNAs expressed in host cells represent a first layer of bioactive encounters that form a part of the cell's overall antiviral arsenal."
On the other hand, viruses, too, encode miRNAs, and they can be used by either the virus or the cell to target viral transcripts. This leads to a
"dynamic strike-counterstrike interplay between cells in which RNAi serves to combat viruses and viruses evade RNAi to successfully replicate in cells."
Interference RNA is not the only way a virus can use to modulate gene expression inside the cell. Once inside the cell, retroviral RNA is turned into DNA which is then transported inside the nucleus and integrated into the host genome. Depending on where in the genome the viral DNA gets integrated, it can promote downstream expression of genes [2]. Oncogenic retroviruses have developed different strategies to induce cellular proliferation and cancer. Some of the human endogenous retroviruses called long terminal repeats (or LTRs, a particular kind of retrotrasnposons, genetic elements of viral origin that are able to transpose to different genome loci) act as promoters for DNA transcription of the nearby genes.
"Retrotransposon-mediated sequence transduction and gene duplication lead to the creation of novel genes and fosters the diversity of multi-gene families such as MHC- or T-cell receptor genes [2]."
For example, it's LTRs that control the expression of retroviral particles in the placenta, something I talked about in one of my very first posts. Upregulation of human endogenous retroviruses gives immunosuppressive properties to the placenta, which are beneficial in preventing allogenic rejection of the fetus. It's truly fascinating that such immunosuppressive properties have been inherited directly from viruses.

[1] Jeang KT (2012). RNAi in the regulation of mammalian viral infections. BMC biology, 10 PMID: 22734679

[2] Reinhard Kurth,, & Norbert Bannert (2010). Beneficial and detrimental effects of human endogenous retroviruses International Journal of Cancer, 126 (2), 306-314 DOI: 10.1002/ijc.24902

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