Functions and Regulation of Endogenous Retrovirus Elements during Zygotic Genome Activation: Implications for Improving Somatic Cell Nuclear Transfer Efficiency

Abstract

Endogenous retroviruses (ERVs), previously viewed as deleterious relics of ancestral retrovirus infections, are silenced in the vast majority of cells to minimize the risk of retrotransposition. Counterintuitively, bursts of ERV transcription usually occur during maternal-to-zygotic transition (MZT) in preimplantation embryos; this is regarded as a major landmark event in the zygotic genome activation (ZGA) process, indicating that ERVs play an active part in ZGA. Evolutionarily, the interaction between ERVs and hosts is mutually beneficial. The endogenization of retrovirus sequences rewires the gene regulatory network during ZGA, and ERV repression may lower germline fitness. Unfortunately, owing to various limitations of somatic cell nuclear transfer (SCNT) technology, both developmental arrest and ZGA abnormalities occur in a high percentage of cloned embryos, accompanied by ERV silencing, which may be caused by the activation failure of upstream ERV inducers. In this review, we discuss the functions and regulation of ERVs during the ZGA process and the feasibility of temporal control over ERVs in cloned embryos via exogenous double homeobox (DUX). We hypothesize that further accurate characterization of the ERV-rewired gene regulatory network during ZGA may provide a novel perspective on the development of preimplantation embryos.

Exploring HERV-K (HML-2) Influence in Cancer and Prospects for Therapeutic Interventions

“…Zygotic genome activation (ZGA) is a critical event in pre-implantation embryo development, where the paternal genome undergoes genome-wide loss of DNA methylation, and H3K4me3 and H4 acetylation occur, leading to transcriptional activation and translational activity during major ZGA-failures in ZGA result in developmental arrest and inability to progress further [40]. Therefore, HERVs are involved in early development by reshaping the gene regulatory network of the preimplantation embryo [41], and their expression is associated with undifferentiated states, phenotypic plasticity, and stem cell characteristics [42], which are traits linked to aggressive cancer and poor patient outcomes. While HERV expression is tightly controlled in normal adult tissues, it is reported to be abnormally expressed in various diseases, including cancer, inflammatory, neurological, aging, and viral infections.…”

“…Thus, HERV-K (HML-2) proviruses can be classified into two sub-types based on the presence or absence of a specific deletion. Type I proviruses express a protein called Np9, while type II proviruses express the Rec protein, which plays a role in RNA transport [41,52]. HERV-K Rec can induce viral restriction pathways in early embryonic cells.…”

Epigenetic manipulation to improve mouse SCNT embryonic development

“…This process is known as ZGA ( Lee et al, 2014 ; Jukam et al, 2017 ; Schulz and Harrison, 2019 ). Reconstructed cloned embryos also undergo ZGA since oocyte cytoplasm can initiate reprogramming when the somatic cell genome is introduced ( Deng et al, 2020 ; Fu et al, 2021 ). Although this reprogramming can result in cloned animals successfully, the insufficient reprogramming by oocyte cytoplasm leads to low efficiency, and many SCNT embryos arrest at the ZGA stage ( Matoba et al, 2014 ; Loi et al, 2016 ; Zhang et al, 2018c ; Deng et al, 2018 ).…”

Transposable Elements in Human Diseases: Evolutionary and Therapeutic Perspectives

“…TE sequences may be transcribed and transposition events occur at di erent levels in di erent cells and tissues of the adult organism, and this may serve important functions. From a species evolution perspective, indeed transpositions in early development, like that of ERVs which were found to have highest expression in oocyte, zygote, and four-cell stages, are most important as these are passed down to future generations in the germline (Lapp and Hunter, 2019;Fu et al, 2021). The acquired roles in their new loci and functions in development and adulthood are key to organism tness and thus have a clear evolutionary role.…”