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RNA fragments defend 'naked' genes

Our genomes, the entire set of genes in our bodies, are minefields studded with potentially damaging DNA sequences. However, our DNA is protected by hundreds of thousands of epigenetic marks which attach to a double helix to identify irregularities and prevent DNA sequences from spontaneously self destructing.


About half of our genome is made up of damaging sequences. Areas where ancient viruses and parasitic elements called transposons and retrotransposons, became incorporated into our DNA during our long evolution. But, astonishingly, during two of the most crucial moments in our life cycle, epigenetic marks are removed, leaving our genome naked and exposed.

Published in Cell, a team from Cold Spring Harbor Laboratory (CSHL) now describes their discovery of what might be considered emergency replacements for epigenetic marks, pressed into service across the genome only during these two moments. One moment being just before the embryo implants in the wall of the uterus when the pre-implantation embryo's epigenetic marks are wiped clean, before being quickly re-instated.

The other moment epigenetic marks are erased is during the formation of germ cells, the sperm and eggs. Germ cells have temporary defenders already known to biologists, so-called piwi-interacting RNAs (piRNAs). The new research led by first author Andrea Schorn as a postdoctoral investigator in the lab of Rob Martienssen a CSHL Professor and Howard Hughes Medical Institute (HHMI) and Gordon and Betty Moore Foundation investigator, revealed that another species of small RNAs act in a similar genome-defender way as do piRNAs in preimplantation embryos.

These newly identified genome-defenders come in two varieties of RNA fragments of 18 or 22 nucleotides or nt — the organic molecules that make up DNA. Mature transfer RNAs (tRNAs) are believed to shed tRFs. The 22 nt tRF silences coding of endogenous retroviruses (ERVs), while 18 nt tRFs specifically interferes with reverse transcription and retrotransposon mobility, or the movement from one genomic location to another.

Dr. Schorn identified these fragments as perfect complements to sequences of retrotransposons. This fact led her to examine the contents of mouse embryonic stem cells where she found many free-floating RNA fragments of 18 nucleotides in length. Computer analysis of these RNA fragments found they perfectly match in length sequences within transfer RNAs (tRNAs), which are ubiquitous as they are involved in the production of proteins. It has been known for decades that tRNAs are hijacked by long terminal repeat (LTR)-retrotransposons.
"We think the cell is deliberately chopping up full-length tRNAs into smaller fragments precisely because both tRNAs and the fragments cut from them recognize primary binding sites (PBS). This means that small, tRNA-derived fragments could occupy that site and inhibit retrotransposon replication and mobility."

Rob Martienssen PhD, Cold Spring Harbor Laboratory, and Howard Hughes Medical Institute, Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.

The implications are potentially profound. "It's plausible that this is a very ancient mechanism that cells have found to not only inhibit retrotransposons but help protect against viruses as well," adds Martienssen.

Highlights
• Highly abundant tRNA fragments (tRF) in mouse stem cells
• 3' CCA tRFs target and inhibit endogenous retroviruses (ERV) active in mouse
• tRFs target the highly conserved primer binding site (PBS) of LTR-retrotransposons
• 18 nt tRFs block reverse transcription; 22 nt tRFs induce RNAi

Summary
Transposon reactivation is an inherent danger in cells that lose epigenetic silencing during developmental reprogramming. In the mouse, long terminal repeat (LTR)-retrotransposons, or endogenous retroviruses (ERV), account for most novel insertions and are expressed in the absence of histone H3 lysine 9 trimethylation in preimplantation stem cells. We found abundant 18 nt tRNA-derived small RNA (tRF) in these cells and ubiquitously expressed 22 nt tRFs that include the 3? terminal CCA of mature tRNAs and target the tRNA primer binding site (PBS) essential for ERV reverse transcription. We show that the two most active ERV families, IAP and MusD/ETn, are major targets and are strongly inhibited by tRFs in retrotransposition assays. 22 nt tRFs post-transcriptionally silence coding-competent ERVs, while 18 nt tRFs specifically interfere with reverse transcription and retrotransposon mobility. The PBS offers a unique target to specifically inhibit LTR-retrotransposons, and tRF-targeting is a potentially highly conserved mechanism of small RNA–mediated transposon control.

Keywords: epigenetic reprogramming, small RNA, tRNA fragments, transposon control, mouse endogenous retroviruses, LTR-retrotransposon mobility


The research discussed was supported by NIH grant R01GM076396; a Bristol-Myers Squibb fellowship from the Watson School of Biological Sciences; the Howard Hughes Medical Institute; the Gordon and Betty Moore Foundation (GMBF3033); and CSHL Cancer Center Support Grant (5PP30CA045508).

About Cold Spring Harbor Laboratory
Founded in 1890, Cold Spring Harbor Laboratory has shaped contemporary biomedical research and education with programs in cancer, neuroscience, plant biology and quantitative biology. Home to eight Nobel Prize winners, the private, not-for-profit Laboratory employs 1,100 people including 600 scientists, students and technicians. The Meetings & Courses Program annually hosts more than 12,000 scientists. The Laboratory's education arm also includes an academic publishing house, a graduate school and the DNA Learning Center with programs for middle and high school students and teachers. For more information, visit http://www.cshl.edu


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In implantation and germ cell formation, RNA fragments cover loss of epigenetic marks.
Image Credit: Rob Martienssen PhD, Cold Spring Harbor Laboratories



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