It’s not how big it is, it’s what you do with it that counts. Here at Epigenie, we don’t think that size matters, as evidenced by our excitement over studies showing that small RNAs in sperm can mediate huge intergenerational effects related to paternal exercise and diet! Now, a fascinating study from the lab of Rob Martienssen (Cold Spring Harbor Laboratory, NY, USA) has discovered a new role for these tiny bits of ribonucleic acid: the protection of the genome during mammalian development!
It turns out that particular species of small transfer RNA fragments (tRFs) can protect the pre-implantation embryo genome from the potentially deleterious activities of transposable elements (TEs). Given the chance, these so-called “jumping genes” will “copy-and-paste” themselves throughout the genome with reckless abandon!
TEs are afforded this enticing opportunity at specific times of human development characterized by the erasure of DNA methylation and histone modifications. The absence of this epigenetic layer of protection allows TEs to become active and potentially wreak havoc through the genome by inducing novel mutations via their copy-and-paste function.
However, Schorn et al. now reveal that small RNA-mediated protection may represent a highly conserved layer of protection to inhibit this potentially deleterious occurrence.
So what are the big details on these small RNAs?
- Analysis of TE-expressing cells, including pre-implantation embryonic stem cells, uncovered a high abundance of transfer RNA-derived small RNA fragments (tRFs)
- Many TEs use transfer RNAs (tRNAs) as primers for reverse transcription
- Small RNA sequencing studies often omit very short RNA fragments and sequencing reads that map to multiple loci and thus discard reads matching the repetitive and numerous TEs
- 18-nucleotide (nt)-long tRFs perfectly match sequences derived from long terminal repeat (LTR)-retrotransposons
- The expression of 18-nt tRFs interferes with the potentially deleterious “copy-and-paste” function of replication-competent retrotransposons via the inhibition of reverse transcription
- The authors confirmed that 18-nt tRFs strongly inhibit the two most active LTR-retrotransposon types in mouse (intracisternal A particle [IAP] and MusD/ early transposon [ETn])
- 22-nucleotide-long tRFs also match sequences in retrotransposons
- This small RNA species targets the tRNA primer binding site (PBS) to post-transcriptionally silence coding-competent retrotransposons
“Knowing that LTR retrotransposons need tRNAs to replicate, it was very tempting to believe that these 18-nucleotide tRNA fragments we were seeing in preimplantation embryonic stem cells could interfere with that process,” says first author Andrea J. Schorn. “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 the primer binding site (PBS). This means the small, tRNA-derived fragments would be able to occupy that site and inhibit retrotransposon replication and mobility,” senior author Rob Martienssen explains.
This all but confirms that size doesn’t matter! However, to size up this new study for yourself, head over to Cell, June 2017.