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

Xuemeng Zhou,Ah Young Lee,Tsz Wing Sam,Danny Leung

doi:10.1038/s41467-021-26630-z

Xuemeng Zhou, Ah Young Lee + Show 2 more

Open Access

https://doi.org/10.1038/s41467-021-26630-z

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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.

Highlights

Polymorphic integrations of endogenous retroviruses (ERVs) have been previously detected in mouse and human genomes
We came across a structural variant defined by the Mouse Genomes Project[42], which was a full-length polymorphic GLN (MMERGLN) element present in C57BL/6 and CBA/J but not in 129S genome assemblies (Fig. 1a)
Syncytin genes are independently derived from speciesspecific ERVs, suggesting a functional but non-sequential conservation by convergent evolution[65]

Summary

Introduction

Polymorphic integrations of endogenous retroviruses (ERVs) have been previously detected in mouse and human genomes. 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 Klhdc[4] gene expression in cis, which alters the activity of downstream stress response genes. A subset of ERVs can escape silencing by participating in normal molecular functions in the host They contribute new protein coding sequences or donate cis-regulatory elements for regulating gene expression in distinct cell types[10,11,12]. We define an extensive list of potential polymorphic ERVs in the genomes of both lines and uncover a subset with epigenetic signatures of cis-regulatory elements Regions adjacent to these elements are associated with concordantly higher transcription and enrichment of active histone modifications. These findings shed light on how polymorphic transposons can introduce new cis-regulatory elements that give rise to inter-individual transcriptomic and phenotypic differences

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