Endogenous Retroviruses Function as Gene Expression Regulatory Elements During Mammalian Pre-implantation Embryo Development

Abstract

Pre-implantation embryo development encompasses several key developmental events, especially the activation of zygotic genome activation (ZGA)-related genes. Endogenous retroviruses (ERVs), which are regarded as "deleterious genomic parasites", were previously considered to be "junk DNA". However, it is now known that ERVs, with limited conservatism across species, mediate conserved developmental processes (e.g., ZGA). Transcriptional activation of ERVs occurs during the transition from maternal control to zygotic genome control, signifying ZGA. ERVs are versatile participants in rewiring gene expression networks during epigenetic reprogramming. Particularly, a subtle balance exists between ERV activation and ERV repression in host⁻virus interplay, which leads to stage-specific ERV expression during pre-implantation embryo development. A large portion of somatic cell nuclear transfer (SCNT) embryos display developmental arrest and ZGA failure during pre-implantation embryo development. Furthermore, because of the close relationship between ERV activation and ZGA, exploring the regulatory mechanism underlying ERV activation may also shed more light on the enigma of SCNT embryo development in model animals.

Keywords: endogenous retroviruses; epigenetic reprogramming; pre-implantation embryo; somatic cell nuclear transfer; zygotic genome activation.

Figure 1

Schematic illustration showing the dynamics of transcription and DNA demethylation during murine pre-implantation embryo development. Shortly after fertilization, embryos undergo extensive global DNA demethylation from the zygote to the blastocyst. Degradation of maternal transcripts is required for ZGA. Minor ZGA occurs at the one-cell stage, while major ZGA takes place at the two-cell stage. Particularly, the expression of MERVL peaks at the two-cell stage, and then gradually decreases until the blastocyst stage.

Figure 2

Schematic illustration showing how pluripotent transcription factors are protected from miRNA-mediated degradation. LincRNA-RoR, a long intergenic noncoding RNA, is transcribed from human endogenous retrovirus subfamily H (HERVH), and then acts as an miRNA sponge to prevent miRNA-mediated degradation of pluripotent transcription factor mRNAs. The intact pluripotent transcription factor mRNAs can then be translated.

Figure 3

Schematic illustration showing how the reverse transcription processes of endogenous retrovirus (ERV) transcripts are repressed. The ERV genes env, gag, and pol are flanked by LTRs that regulate ERV transcription. The 3′terminus of intact mature tRNA is used as the special primer to complete the reverse transcription process. However, the process is interrupted when 18-nt 3′-tRF (tRNA-derived fragment) binds to the primer binding site.

Figure 4

Schematic illustration showing how endogenous retrovirus (ERVs) activation is controlled by double homeobox DUX during murine pre-implantation development. After fertilization, a globally transcriptionally permissive state caused by the loosening of chromatin activates DUX. Then, DUX drives the expression of zygotic genome activation (ZGA)-related genes such as Zscan4 and regulates ERV activation. LINE 1 RNA represses DUX by recruiting Nucleolin/Kap1, thereby indirectly repressing ZGA-related genes and ERV elements. This allows 2-cell embryos to develop into the 4-cell state. In contrast, LINE 1 knockdown (KD) causes persistence of the 2-cell state and failure of ZGA.