Transposable elements, often considered to be not important for survival, significantly contribute to the evolution of transcriptomes, promoters, and proteomes. Reverse transcriptase, encoded by some transposable elements, can be used in trans to produce a DNA copy of any RNA molecule in the cell. The retrotransposition of protein-coding genes requires the presence of reverse transcriptase, which could be delivered by either non-long terminal repeat (non-LTR) or LTR transposons. The majority of these copies are in a state of “relaxed” selection and remain “dormant” because they are lacking regulatory regions; however, many become functional. In the course of evolution, they may undergo subfunctionalization, neofunctionalization, or replace their progenitors. Functional retrocopies (retrogenes) can encode proteins, novel or similar to those encoded by their progenitors, can be used as alternative exons or create chimeric transcripts, and can also be involved in transcriptional interference and participate in the epigenetic regulation of parental gene expression. They can also act in trans as natural antisense transcripts, microRNA (miRNA) sponges, or a source of various small RNAs. Moreover, many retrocopies of protein-coding genes are linked to human diseases, especially various types of cancer.

Retroposition is RNA-based gene duplication leading to the creation of single exon nonfunctional copies. Nevertheless, over time, many of these duplicates acquire transcriptional capabilities. In human in most cases, these so-called retrogenes do not code for proteins but function as regulatory long noncoding RNAs (lncRNAs). The mechanisms by which they can regulate other genes include microRNA sponging, modulation of alternative splicing, epigenetic regulation and competition for stabilizing factors, among others. Here, we summarize recent findings related to lncRNAs originating from retrocopies that are involved in human diseases such as cancer and neurodegenerative, mental or cardiovascular disorders. Special attention is given to retrocopies that regulate their progenitors or host genes. Presented evidence from the literature and our bioinformatics analyses demonstrates that these retrocopies, often described as unimportant pseudogenes, are significant players in the cell’s molecular machinery.

Gene duplication is a major driver of organismal evolution. One of the main mechanisms of gene duplications is retroposition, a process in which mRNA is first transcribed into DNA and then reintegrated into the genome. Most gene retrocopies are depleted of the regulatory regions. Nevertheless, examples of functional retrogenes are rapidly increasing. These functions come from the gain of new spatio-temporal expression patterns, imposed by the content of the genomic sequence surrounding inserted cDNA and/or by selectively advantageous mutations, which may lead to the switch from protein coding to regulatory RNA. As recent studies have shown, these genes may lead to new protein domain formation through fusion with other genes, new regulatory RNAs or other regulatory elements. We utilized existing data from high-throughput technologies to create a complex description of retrogenes functionality. Our analysis led to the identification of human retroposed genes that substantially contributed to transcriptome and proteome. These retrocopies demonstrated the potential to encode proteins or short peptides, act as cis- and trans- Natural Antisense Transcripts (NATs), regulate their progenitors’ expression by competing for the same microRNAs, and provide a sequence to lncRNA and novel exons to existing protein-coding genes. Our study also revealed that retrocopies, similarly to retrotransposons, may act as recombination hot spots. To our best knowledge this is the first complex analysis of these functions of retrocopies.

A large portion of the human genome is transcribed into long noncoding RNAs that can range from 200 nucleotides to several kilobases in length. The number of identified lncRNAs is still growing, but only a handful of them have been functionally characterized. However, it is known that the functions of lncRNAs are closely related to their subcellular localization. Cytoplasmic lncRNAs can regulate mRNA stability, affect translation and act as miRNA sponges, while nuclear-retained long noncoding RNAs have been reported to be involved in transcriptional control, chromosome scaffolding, modulation of alternative splicing and chromatin remodelling. Through these processes, lncRNAs have diverse regulatory roles in cell biology and diseases. OIP5-AS1 (also known as Cyrano), a poorly characterized lncRNA expressed antisense to the OIP5 oncogene, is deregulated in multiple cancers. We showed that one of the OIP5-AS1 splicing forms (ENST00000501665.2) is retained in the cell nucleus where it associates with chromatin, thus narrowing down the spectrum of its possible mechanisms of action. Its knockdown with antisense LNA gapmeRs led to inhibited expression of a sense partner, OIP5, strongly suggesting a functional coupling between OIP5 and ENST00000501665.2. A subsequent bioinformatics analysis followed by RAP-MS and RNA Immunoprecipitation experiments suggested its possible mode of action; in particular, we found that ENST00000501665.2 directly binds to a number of nuclear proteins, including SMARCA4, a component of the SWI/SNF chromatin remodelling complex, whose binding motif is located in the promoter of the OIP5 oncogene.