LTR-Retrotransposon Control by tRNA-Derived Small RNAs

Area of Science:

• Molecular Biology
• Genetics
• Epigenetics

Background:

• Transposon reactivation poses a risk during cellular reprogramming when epigenetic silencing is lost.
• Long terminal repeat (LTR)-retrotransposons, or endogenous retroviruses (ERVs), are a major source of novel insertions in mouse cells lacking specific histone modifications.

Purpose of the Study:

• To investigate the role of tRNA-derived small RNAs (tRFs) in controlling endogenous retrovirus (ERV) activity.
• To identify the specific targets and mechanisms by which tRFs regulate retrotransposon mobility.

Main Methods:

• Analysis of small RNA populations in preimplantation stem cells.
• In vitro retrotransposition assays to assess ERV inhibition by tRFs.
• Identification of tRNA-derived small RNA (tRF) targets within ERV sequences.

Main Results:

• Abundant 18 nt and ubiquitously expressed 22 nt tRFs were identified.
• These tRFs target the primer binding site (PBS) crucial for ERV reverse transcription.
• tRFs significantly inhibited the retrotransposition of major ERV families (IAP, MusD/ETn).

Conclusions:

• tRFs act as a defense mechanism against transposon reactivation by interfering with ERV replication.
• 22 nt tRFs post-transcriptionally silence coding ERVs, while 18 nt tRFs inhibit reverse transcription and mobility.
• Targeting the PBS is a specific strategy to inhibit LTR-retrotransposons, suggesting a conserved small RNA-mediated transposon control mechanism.