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Not so pseudo anymore: pseudogenes as therapeutic targets - PubMed

Not so pseudo anymore: pseudogenes as therapeutic targets

Thomas C Roberts et al. Pharmacogenomics. 2013 Dec.

Abstract

Pseudogenes are junk DNA gene remnants generated by inactivating mutations or the loss of regulatory sequences, often following gene duplication or retrotransposition events. These pseudogenes have previously been considered to be molecular fossils derived from once-coding genes. In many cases, pseudogenes confer no observable selective advantage to the host organism and may be on a path towards removal from the genome. However, pseudogenes can also serve as raw material for the exaptation of novel functions, particularly in relation to the regulation of gene expression. Many pseudogenes are resurrected as noncoding RNA genes, which function in RNA-based gene regulatory circuits. As such, functional pseudogenes might simply be considered as 'genes'. Here, we discuss the role of these pseudogene-derived RNAs as regulators of gene expression in the context of human disease. In particular, we consider the manipulation of pseudogene transcripts through the use of antisense oligonucleotides, siRNAs, aptamers or classical gene therapy approaches as novel pharmacological strategies.

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Conflict of interest statement

Financial & competing interests disclosure

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Figures

Figure 1
Figure 1. Biogenesis and transcription of pseudogenes

(A) There are three types of pseudogene. Unitary pseudogenes are formed when the parental gene is degraded by mutations (indicated in red). Duplicated pseudogenes are produced when a gene loci is copied, often to a site proximal to the parental gene. The gene copy is subsequently pseudogenized by inactivating mutations. Processed pseudogenes are generated when an mRNA is reverse transcribed and then integrated back into the genome. As a result, processed pseudogenes lack the intron–exon structure and upstream regulatory regions of the parental gene. (B) Some pseudogenes are transcribed. This can occur when transcription is driven by duplicated upstream regulatory regions (i.e., promoter or enhancer sequences). Conversely, processed pseudogenes may integrate in sites adjacent to regulatory elements. Pseudogene transcription can occur in both sense and antisense orientations. Please see color figure at

www.futuremedicine.com/doi/pdf/10.2217/pgs.13.172

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Figure 2
Figure 2. Post-transcriptional pseudogene regulation

(A) Pseudogene transcripts can compete with their cognate parental mRNAs for RNA stability factors. For example, HMGA1 mRNA and its pseudogene (HMGA1-p) contain a common 3´ decay element that binds to the stability factor αCP1. (B) Pseudogene transcripts can also interact directly with the parental mRNA to influence its expression. For example, nNOS mRNA hybridizes with an antisense nNOS pseudogene transcript (nNOS-p), which results in suppression of nNOS translation.

Figure 3
Figure 3. Crosstalk between pseudogenes and the RNAi pathway

Pseudogene transcripts are sources of endo-siRNA clusters. (A) Pseudogene transcripts can fold into long hairpin structures that are processed by Dicer into approximately 21-bp endo-siRNA duplexes. Endo-siRNA-producing Dicer substrates are also generated when (B) the parental mRNA binds with an antisense pseudogene transcript or when (C) complementary sense and antisense transcripts derived from pseudogene loci hybridize. Endo-siRNAs produced by these mechanisms are complementary to the paralogous parental gene and act to regulate its expression at the post-transcriptional level. (D) Pseudogene transcripts can act as ceRNAs by competing with their parental mRNAs for miRNA binding. ceRNA: Competing endogenous RNA.

Figure 4
Figure 4. Pseudogene-mediated epigenetic control

Antisense pseudogene transcripts bind to epigenetic modifying factors (e.g., EZH2 and DNMT3A) and recruit them to the parental gene locus, leading to heterochromatinization (compact histones are indicated in turquoise) and DNA methylation (dark blue lollipops) of the promoter region. As a result, the parental gene is silenced at the transcriptional level. Please see color figure at

www.futuremedicine.com/doi/pdf/10.2217/pgs.13.172

.

Figure 5
Figure 5. Oligonucleotides for therapeutic targeting of pseudogene transcripts

(A) Gapmer AOs consist of a central DNA-based core with flanking RNA or LNA sequences. Binding to a target transcript induces the formation of an RNA-DNA duplex, which is a substrate for RNase H-mediated degradation. (B) Mixmer AOs consist of alternating nucleic acid chemistries and act to sterically block association of the target transcript with proteins or other nucleic acids. (C) siRNAs are effectors of the RNAi pathway. A typical siRNA consists of a 19-bp RNA duplex with two-nucleotide (RNA or DNA) 3´ overhangs. (D) Structure of a typical RNA aptamer. (E) Common nucleic acid chemistries utilized in AOs, siRNAs and aptamers include modifications to the backbone (e.g., phosphorothioate linkages, PS-RNA), substitutions at the 2´ position of the ribose ring (e.g., 2’-O-methyl and 2´-fluoro) and the use of bicyclic nucleotides (e.g., LNA). AO: Antisense oligonucleotide; LNA: Locked nucleic acid; PS-RNA: Phosphorothioate RNA.

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