What do the mammalian genome and an old storage unit have in common? They’re both full of so-called junk. But unlike your aunt’s box of glass figurines, the junk in the human genome has turned out to have a lot of value. Most the “junk” in the human genome arose from retrotransposons. Long terminal repeat (LTR) retrotransposons are normally epigenetically repressed; however, some are active in germ cells and early embryos. In oocytes, many transcripts originate in LTRs. LTRs are evolutionarily heterogeneous, differing even between closely related species.
The laboratory of Matthew Lorincz at the University of British Columbia sought to investigate the extent to which LTR-initiated transcripts (LITs) impact DNA methylation in mouse, rat, and human oocytes. In an extensive new paper, they utilized whole-genome bisulfite sequencing (WGBS) and RNA-seq to examine DNA methylation and gene expression, respectively, in these three mammalian species. They identified thousands of syntenic LTR regions (sequence and gene order conserved between species) and examined how expression from these regions (LITs) affected DNA methylation. To determine the relationship between DNA methylation and expression at LTRS, they correlated the DNA methylation and expression data within and across each species.
Here’s what they found:
- DNA methylation is much more similar in sperm than in oocytes across syntenic genomic regions
- Genic regions show much more similar methylation profiles than intergenic regions across species
- Many LITs transcribed from syntenic regions are species-specific and associated with downstream species-specific de novo DNA methylation
- Especially those in intergenic regions
- LITs also coincide with H3K36me3 deposition
- By examining polymorphisms in LTRs between two mouse stains, they uncovered strain-specific LITs, which show a clear bias in both transcription and DNA methylation, meaning they likely affect strain-specific DNA methylation
- LTR DNA methylation persists at specific sites of the maternal genome after fertilization in mice and humans,
Understanding how LTRs function is important for understanding the regulation of many germ cell-specific genes, as many LTR families have been incorporated by the host genome into serving as germ-cell-specific promoters.
Dr. Lorincz shares “As many of the observed LITs are species-specific, this phenomenon may explain phenotypic differences observed between species and even with a species, such as in mice, where these LTR retrotransposons are particularly active and occupy distinct genomic regions depending on the mouse strain.”
Following up on the persistent DNA methylation in oocytes, their future work will involve investigating the role of LTRs in establishing imprinting. Overall, this work has further dispelled the notion of LTRs as useless sequences; since when it comes to junk DNA, a somatic cells’ trash is a germ cells’ treasure.
Check out the full story in Nature Communications, August 2018