Long terminal repeats power evolution of genes and gene expression programs in mammalian oocytes and zygotes

Abstract

Retrotransposons are "copy-and-paste" insertional mutagens that substantially contribute to mammalian genome content. Retrotransposons often carry long terminal repeats (LTRs) for retrovirus-like reverse transcription and integration into the genome. We report an extraordinary impact of a group of LTRs from the mammalian endogenous retrovirus-related ERVL retrotransposon class on gene expression in the germline and beyond. In mouse, we identified more than 800 LTRs from ORR1, MT, MT2, and MLT families, which resemble mobile gene-remodeling platforms that supply promoters and first exons. The LTR-mediated gene remodeling also extends to hamster, human, and bovine oocytes. The LTRs function in a stagespecific manner during the oocyte-to-embryo transition by activating transcription, altering protein-coding sequences, producing noncoding RNAs, and even supporting evolution of new protein-coding genes. These functions result, for example, in recycling processed pseudogenes into mRNAs or lncRNAs with regulatory roles. The functional potential of the studied LTRs is even higher, because we show that dormant LTR promoter activity can rescue loss of an essential upstream promoter. We also report a novel protein-coding gene evolution-D6Ertd527e-in which an MT LTR provided a promoter and the 5

Low miRNA abundance disables microRNA pathway in mammalian oocytes

“…Limiting amount of AGO2 could explain reduced miRNA levels. However, this alternative processing of Ago2 transcript is not observed in other examined mammalian oocytes whose transcriptomes were sequenced 40,41 . Thus, other mammals would have to independently evolve other mechanism(s) restricting the miRNA pathway via expression of AGO proteins.…”

“…Thus, other mammals would have to independently evolve other mechanism(s) restricting the miRNA pathway via expression of AGO proteins. Alternatively, mouse AGO2 regulation reported by Freimer et al 25 could be an adaptation restricting the endogenous RNAi pathway, which is highly active in mouse oocytes and has been specifically evolving in the mouse lineage 37,41,52 .…”

“…It could be possible that mouse oocytes represent a unique case where miRNAs do not accumulate because they compete with siRNAs for limited amount of AGO proteins. To examine this possibility, we quantified maternal miRNAs in four other mammalian species, including bovine and hamster oocytes where the truncated Ago2 transcript does not exist according to RNA-seq data 40,41 . Analysis of rat, golden hamster, bovine, and porcine oocytes showed miRNA tallies similar to those in mouse oocytes (Fig.…”

Epigenomic and single-cell profiling of human spermatogonial stem cells

“…These elements belong to a superfamily of endogenous retrovirus, the ERV1 superfamily. In mice, transcription of another superfamily of endogenous retrovirus ERVL was associated with germline expression during spermatogenesis and oogenesis (26,27). However, association of ERV1 in gametogenesis has not been reported.…”

The PIWI/piRNA response is relaxed in a rodent that lacks mobilizing transposable elements

“…Because of their ability to mobilize, TEs are powerful mutagens as novel TE insertions can disrupt exons, regulatory elements, and splice junctions, and also facilitate non-homologous recombination. As a result, TE insertions have been linked to genomic deletions, duplications, inversions, translocations, and chromosome breaks in a variety of genomes (Cheng et al 2005;Franke et al 2017;Platt et al 2018). Although some TE insertions have proven to be adaptive, TEs are generally considered a serious challenge to genome integrity.…”