Abstract
The competitive endogenous RNA (ceRNA) hypothesis is an attractively simple model to explain the biological role of many putatively functionless noncoding RNAs. Under this model, there exist transcripts in the cell whose role is to titrate out microRNAs such that the expression level of another target sequence is altered. That it is logistically possible for expression of one microRNA recognition element (MRE)-containing transcript to affect another is seen in the multiple examples of pathogenic effects of inappropriate expression of MRE-containing RNAs. However, the role, if any, of ceRNAs in normal biological processes and at physiological levels is disputed. By comparison of parent genes and pseudogenes we show, both for a specific example and genome-wide, that the pseudo-3′ untranslated regions (3′UTRs) of expressed pseudogenes are frequently retained and are under selective constraint in mammalian genomes. We found that the pseudo-3′UTR of BRAFP1, a previously described oncogenic ceRNA, has reduced substitutions relative to its pseudo-coding sequence, and we show sequence constraint on MREs shared between the parent gene, BRAF, and the pseudogene. Investigation of RNA-seq data reveals expression of BRAFP1 in normal somatic tissues in human and in other primates, consistent with biological ceRNA functionality of this pseudogene in nonpathogenic cellular contexts. Furthermore, we find that on a genome-wide scale pseudo-3′UTRs of mammalian pseudogenes (n = 1,629) are under stronger selective constraint than their pseudo-coding sequence counterparts, and are more often retained and expressed. Our results suggest that many human pseudogenes, often considered nonfunctional, may have an evolutionarily constrained role, consistent with the ceRNA hypothesis.
Highlights
The 30 untranslated regions (30UTRs) of BRAFP1 Exhibits Evolutionary Sequence Constraint in Catarrhini Primates Pseudogenes of the oncogene BRAF are present in human (BRAFP1) and in mouse (Braf-rs1), and these processed pseudogenes are capable of functioning as oncogenic competitive endogenous RNA (ceRNA) in both of these species
We confirm that the genomic locations of BRAFP1 and Braf-rs1 are not syntenic, and that the pseudogenes share greater sequence similarity to the BRAF parent genes (88.5% and 85.9% in human and mouse, respectively) than to each other (57.8%)
There has been substantial interest in the ceRNA hypothesis in recent years, with much of the research in the area revolving around how dysregulation of ceRNA expression can affect cancer pathogenicity and progression (Poliseno et al 2010; Karreth et al 2011, 2015; Poliseno and Pandolfi 2015)
Summary
The competitive endogenous RNA (ceRNA) hypothesis proposes that RNAs, expressed concurrently and with a similar complement of microRNA (miRNA) recognition elements (MREs), are capable of indirectly regulating one another by competing for a shared, limited pool of miRNA molecules (Seitz 2009; Poliseno et al 2010; Salmena et al 2011; Thomson and Dinger 2016). CeRNAs can be noncoding transcripts such as long noncoding RNAs (lncRNAs), circular RNAs, or expressed pseudogenes These transcripts are capable of sequestering miRNAs that otherwise would have targeted protein-coding mRNAs, and reduce the amount of mRNA undergoing miRNA-mediated degradation and/or repression of translation initiation. Copy number loss of PTENP1 and copy number gain of BRAFP1 have been associated with their respective tumor suppressive and oncogenic potential (Poliseno et al 2010; Karreth et al 2015) Additional pseudogenes, such as KRASP1, TUSC2P, OCT4P4, CYP4Z2P, GBAP1, and BCAS4 (a unitary pseudogene), have been shown to exert a ceRNA effect, most often by regulating their parent gene’s expression (Poliseno et al 2010; Marques et al 2012; Wang, Guo, et al 2013; Rutnam et al 2014; Zheng et al 2015, 2016; Straniero et al 2017). Dysregulation of expression of these pseudogenes can result in pathogenic consequences
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