Mouse strain-specific polymorphic provirus functions as cis-regulatory element leading to epigenomic and transcriptomic variations

Abstract

Polymorphic integrations of endogenous retroviruses (ERVs) have been previously detected in mouse and human genomes. While most are inert, a subset can influence the activity of the host genes. However, the molecular mechanism underlying how such elements affect the epigenome and transcriptome and their roles in driving intra-specific variation remain unclear. Here, by utilizing wildtype murine embryonic stem cells (mESCs) derived from distinct genetic backgrounds, we discover a polymorphic MMERGLN (GLN) element capable of regulating H3K27ac enrichment and transcription of neighboring loci. We demonstrate that this polymorphic element can enhance the neighboring Klhdc4 gene expression in cis, which alters the activity of downstream stress response genes. These results suggest that the polymorphic ERV-derived cis-regulatory element contributes to differential phenotypes from stimuli between mouse strains. Moreover, we identify thousands of potential polymorphic ERVs in mESCs, a subset of which show an association between proviral activity and nearby chromatin states and transcription. Overall, our findings elucidate the mechanism of how polymorphic ERVs can shape the epigenome and transcriptional networks that give rise to phenotypic divergence between individuals.

Transposable elements acquire time- and sex-specific transcriptional and epigenetic signatures along mouse fetal gonad development

“…As such, they potentially contribute to the specie-specific characteristics of TESCO activity. In the same line, several studies have shown that TEs are highly heterogeneous between mouse strains (Nellaker et al, 2012;Jung et al, 2023) that can modify gene expression (Zhou et al, 2021) and chromatin dynamics (Ferraj et al, 2023). Therefore, we can speculate that strain-specific TEs could be involved in the sensitivity of a C57BL/6J background to sex reversal (Eicher et al, 1982;Eicher et al, 1996;Munger et al, 2009).…”

Transposable elements acquire time- and sex-specific transcriptional and epigenetic signatures along mouse fetal gonad development

“…As such, they potentially contribute to species-specific characteristics of TESCO activity. In the same line, several studies have shown that TEs are highly heterogenous between mouse strains (Jung et al 2023, Nellaker et al 2012) that can modify the genes expression (Zhou et al 2021) and chromatin dynamic (Ferraj et al 2023). Therefore, we can speculate that strain-specific TEs could be involved in the sensitivity of C57BL/6J background to sex reversal (Eicher et al 1996, Eicher et al 1982, Munger et al 2009).…”

The Molecular Impacts of Retrotransposons in Development and Diseases

“…However, findings related to TEVs have limitations in translational research due to the influence of polymorphic ERVs on intra-species divergence [143]. To address this challenge, the innovation of sequencing technologies, such as long-read sequencing, has identified nearly twice as many new TEVs, some of which are associated with phenotypic differences.…”