An ancient retroviral RNA element hidden in mammalian genomes and its involvement in co-opted retroviral gene regulation

Koichi Kitao,So Nakagawa,Takayuki Miyazawa

doi:10.1186/s12977-021-00580-2

Abstract

BackgroundRetroviruses utilize multiple unique RNA elements to control RNA processing and translation. However, it is unclear what functional RNA elements are present in endogenous retroviruses (ERVs). Gene co-option from ERVs sometimes entails the conservation of viral cis-elements required for gene expression, which might reveal the RNA regulation in ERVs.ResultsHere, we characterized an RNA element found in ERVs consisting of three specific sequence motifs, called SPRE. The SPRE-like elements were found in different ERV families but not in any exogenous viral sequences examined. We observed more than a thousand of copies of the SPRE-like elements in several mammalian genomes; in human and marmoset genomes, they overlapped with lineage-specific ERVs. SPRE was originally found in human syncytin-1 and syncytin-2. Indeed, several mammalian syncytin genes: mac-syncytin-3 of macaque, syncytin-Ten1 of tenrec, and syncytin-Car1 of Carnivora, contained the SPRE-like elements. A reporter assay revealed that the enhancement of gene expression by SPRE depended on the reporter genes. Mutation of SPRE impaired the wild-type syncytin-2 expression while the same mutation did not affect codon-optimized syncytin-2, suggesting that SPRE activity depends on the coding sequence.ConclusionsThese results indicate multiple independent invasions of various mammalian genomes by retroviruses harboring SPRE-like elements. Functional SPRE-like elements are found in several syncytin genes derived from these retroviruses. This element may facilitate the expression of viral genes, which were suppressed due to inefficient codon frequency or repressive elements within the coding sequences. These findings provide new insights into the long-term evolution of RNA elements and molecular mechanisms of gene expression in retroviruses.

Highlights

Retroviruses utilize multiple unique RNA elements to control RNA processing and translation
Functional syncytin posttranscriptional regulatory element (SPRE)-like elements are found in several syncytin genes derived from these retroviruses
We previously reported that an RNA element located in the 3′ end of the protein-coding sequence and 3′ untranslated region (3′ Untranslated region (UTR)) of human syncytin-1 is important for its protein expression and was named syncytin posttranscriptional regulatory element (SPRE) [21]

Summary

Introduction

Retroviruses utilize multiple unique RNA elements to control RNA processing and translation. Gene co-option from ERVs sometimes entails the conservation of viral cis-elements required for gene expression, which might reveal the RNA regulation in ERVs. Just as the traces of ancient organisms remain as fossils, traces of ancient retroviruses remain as DNA sequences in host genomes. The binding of Rev to RRE facilitates the export of un-spliced viral RNA to the cytoplasm with the host factor CRM1/ XPO1 [6] as well as the translation of Env and regulatory and accessory proteins [7]. It was revealed that the binding of the host protein TAP/NXF1 to CTE promotes nuclear transport and the translation of unspliced viral RNA [11, 12]. Retroviruses have complex RNA elements in their short genomes that allow them to replicate efficiently

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