Chromatin modifier HUSH co-operates with RNA decay factor NEXT to restrict transposable element expression

Area of Science:

• Molecular Biology
• Epigenetics
• Genetics

Background:

• Transposable elements (TEs) are mobile genetic sequences that can disrupt genomes.
• Transcriptional control and RNA decay pathways are crucial for suppressing TE activity.
• The nuclear exosome targeting (NEXT) and human silencing hub (HUSH) complexes are key regulators in RNA processing and epigenetic silencing.

Purpose of the Study:

• To investigate the functional relationship between the NEXT and HUSH complexes in regulating transposable elements.
• To elucidate the molecular mechanisms underlying the synergistic action of NEXT and HUSH in controlling TE expression.

Main Methods:

• Zygotic ZCCHC8 knockout in mouse embryonic stem cells.
• Co-immunoprecipitation to identify protein interactions.
• RNA sequencing to quantify transcript levels.
• Chromatin immunoprecipitation to assess HUSH and NEXT recruitment to TE loci.

Main Results:

• ZCCHC8 knockout led to increased transposable element RNA levels.
• A physical interaction between ZCCHC8 (NEXT) and MPP8 (HUSH) was identified.
• HUSH complex recruits the NEXT complex to chromatin at specific TE locations.
• NEXT and HUSH exhibit distinct but complementary roles in suppressing TE transcripts (non-polyadenylated vs. polyadenylated).

Conclusions:

• The HUSH complex facilitates the recruitment of the NEXT complex to TE loci.
• Synergistic action of transcriptional (HUSH) and post-transcriptional (NEXT) regulation suppresses TE expression.
• This coordinated mechanism prevents the genotoxic potential of transposable elements.