Structure and Expression of Mobile ETnII Retroelements and Their Coding-Competent MusD Relatives in the Mouse

Abstract

ETnII elements are mobile members of the repetitive early transposon family of mouse long terminal repeat (LTR) retroelements and have caused a number of mutations by inserting into genes. ETnII sequences lack retroviral genes, but the recent discovery of related MusD retroviral elements with regions similar to gag, pro, and pol suggests that MusD provides the proteins necessary for ETnII transposition in trans. For this study, we analyzed all ETnII elements in the draft sequence of the C57BL/6J genome and classified them into three subtypes (␣, ␤, and ␥) based on structural differences. We then used database searches and quantitative real-time PCR to determine the copy number and expression of ETnII and MusD elements in various mouse strains. In 7.5-day-old embryos of a mouse strain in which two mutations due to ETnII-␤ insertions have been identified (SELH/Bc), we detected a three-to sixfold higher level of ETnII-␤ and MusD transcripts than in control strains (C57BL/6J and LM/Bc). The increased ETnII transcription level can in part be attributed to a higher number of ETnII-␤ elements, but 70% of the MusD transcripts appear to have been derived from one or a few MusD elements that are not detectable in C57BL/6J mice. This element belongs to a young MusD subgroup with intact open reading frames and identical LTRs, suggesting that the overexpressed element(s) in SELH/Bc mice might provide the proteins for the retrotransposition of ETnII and MusD elements. We also show that ETnII is expressed up to 30-fold more than MusD, which could explain why only ETnII, but not MusD, elements have been positively identified as new insertions.

A unique configuration of genome-wide DNA methylation patterns in the testis

“…In the mouse, NotI sites are found within some interspersed repetitive elements, predominantly in the internal sequence of intracisternal-A particle (IAP) and in the long terminal repeats (LTRs) of early transposon (ETn) and other LTR-containing families of repeat sequences (18)(19)(20). All unchanged unmethylated loci were found solely within nonrepetitive sequences, whereas approximately one-half of the unchanged methylated loci were found to be within various interspersed repeats, particularly IAP (Table 1).…”

Genome-wide maps of chromatin state in pluripotent and lineage-committed cells

“…IAP and ETn elements are active in murine ES cells and produce double-stranded RNAs 41,42 . RNA has also been implicated in maintaining satellite and telomeric heterochromatin 38 .…”

Consequences of ongoing retrotransposition in mammalian genomes

“…23,45 IAP RNA is present in male germ cells, oocytes, ovulated eggs, very early embryos, and at reduced levels as preimplantation development progresses. 28,38,[46][47][48] Limited somatic expression of IAP may be restricted to particular individual elements based on their genomic context. 23 MusD transcripts are expressed early in embryogenesis, at reduced levels as embryogenesis proceeds, in mouse ES cells, and at elevated levels in skeletal muscle and liver of aged mice.…”

“…23 MusD transcripts are expressed early in embryogenesis, at reduced levels as embryogenesis proceeds, in mouse ES cells, and at elevated levels in skeletal muscle and liver of aged mice. 28,40 Retrotransposition in humans and mice occurs in primordial germ cells, germ cells, and/or early embryos, based on inheritance of spontaneous insertion mutations, but it also occurs to some extent in somatic cells. Identification that the mother of a patient with a disease-causing L1 insertion allele was a somatic and germ line mosaic for the insertion allele is consistent with retrotransposition during early development.…”

“…24 MusD mobilizes the related nonautonomous early transposon (ETn) element (Figures 1 and 2), which also requires all three MusD gene functions and results from sequence similarity between MusD and ETn LTRs, primer binding sites, and polypurine tract sequences. 25,28 Developmental timing and tissue specificity of mammalian retrotransposition Proteins of autonomous retrotransposons are necessary for retrotransposition, so expression of these elements determines the potential times and cell types in which retrotransposition can occur. L1 RNA is present in human and rodent germ cells (male and female), embryonic stem (ES) cells, neural progenitor cells, cancer cells/tumors, in mouse preimplantation embryos, and in a variety of human somatic tissues.…”