Inter-Strain Epigenomic Profiling Reveals a Candidate IAP Master Copy in C3H Mice.

Rita Rebollo,Ardian Ferraj,Matthew C Lorincz,Liane Gagnier,Christine R Beck,Dixie L Mager,Mariana Galvão-Ferrarini,Ying Zhang

doi:10.3390/v12070783

Abstract

Insertions of endogenous retroviruses cause a significant fraction of mutations in inbred mice but not all strains are equally susceptible. Notably, most new Intracisternal A particle (IAP) ERV mutagenic insertions have occurred in C3H mice. We show here that strain-specific insertional polymorphic IAPs accumulate faster in C3H/HeJ mice, relative to other sequenced strains, and that IAP transcript levels are higher in C3H/HeJ embryonic stem (ES) cells compared to other ES cells. To investigate the mechanism for high IAP activity in C3H mice, we identified 61 IAP copies in C3H/HeJ ES cells enriched with H3K4me3 (a mark of active promoters) and, among those tested, all are unmethylated in C3H/HeJ ES cells. Notably, 13 of the 61 are specific to C3H/HeJ and are members of the non-autonomous 1Δ1 IAP subfamily that is responsible for nearly all new insertions in C3H. One copy is full length with intact open reading frames and hence potentially capable of providing proteins in trans to other 1Δ1 elements. This potential “master copy” is present in other strains, including 129, but its 5’ long terminal repeat (LTR) is methylated in 129 ES cells. Thus, the unusual IAP activity in C3H may be due to reduced epigenetic repression coupled with the presence of a master copy.

Highlights

Transposable elements (TEs) are repeated DNA sequences that are generally grouped into two classes depending on their transposition mechanism: retrotransposons copy themselves within the genome through an RNA intermediate, while DNA elements transpose directly via a DNA molecule.TEs have been observed in most genomes analyzed to date, attesting to their effectiveness at colonizing host genomes and contributing to genome size variation and diversity between and within species [1,2]
If Intracisternal A-particle sequences (IAP) elements have been active in C3H mice since strain divergence, private IAP copies that are not highly detrimental would accumulate at a faster rate in C3H, compared to other strains
We have shown that IAP insertions are accumulating more rapidly in C3H/HeJ compared to other sequenced strains, which is in accord with the fact that most documented germ line mutations due to new IAP insertions have occurred in C3H/HeJ or other C3H sub-strains [8]

Summary

Introduction

Transposable elements (TEs) are repeated DNA sequences that are generally grouped into two classes depending on their transposition mechanism: retrotransposons copy themselves within the genome through an RNA intermediate, while DNA elements transpose directly via a DNA molecule.TEs have been observed in most genomes analyzed to date, attesting to their effectiveness at colonizing host genomes and contributing to genome size variation and diversity between and within species [1,2]. TEs spread genome-wide regulatory sequences present within their copies, allowing for the establishment of gene regulatory networks and playing an important role in host genetic programs [3,4]. TEs are a major ongoing mutagenic source, responsible for up to 14–16%. Of all published germ-line mutations in inbred strains [6,7,8]. The majority of mouse TE insertional mutations are caused by endogenous retroviruses (ERVs), which are signatures of past retroviral infections of the germ-line that integrated into the host genome and adopted an endogenous life-cycle [7,8]. Around 10% of the mouse genome is composed of ERV sequences of many different families [6,9]. Intracisternal A-particle sequences (IAP) [10], a particular ERV family, is responsible for

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Conclusion