The nuclear exosome co-factor MTR4 shapes the transcriptome for meiotic initiation

Area of Science:

• Molecular Biology
• Developmental Biology
• Genetics

Background:

• Nuclear RNA decay is a known post-transcriptional gene regulation mechanism in cultured cells.
• Its occurrence and biological significance in animals, particularly during development and reproduction, remain largely uninvestigated.

Purpose of the Study:

• To investigate the role of MTR4, a central cofactor of the nuclear RNA exosome, in animal embryogenesis and spermatogenesis.
• To elucidate the mechanisms by which MTR4/exosome regulates gene expression in germ cells during the transition from mitosis to meiosis.

Main Methods:

• Generation and analysis of Mtr4 knockout mice (embryonic and germ cell-specific).
• Transcriptomic analysis to identify MTR4/exosome targets and regulatory functions.
• Investigation of RNA degradation and alternative splicing pathways.

Main Results:

• Mtr4 knockout mice exhibit embryonic lethality by 6.5 days and male infertility due to defects in meiotic initiation.
• MTR4/exosome actively represses meiotic genes and ensures mitotic gene expression in pre-meiotic germ cells via RNA degradation.
• Identified mature histone mRNAs and retrotransposon RNAs as MTR4/exosome targets; MTR4 also influences alternative splicing of meiotic genes.

Conclusions:

• Nuclear RNA degradation mediated by MTR4/exosome is essential for embryogenesis and male germline development.
• This pathway plays a critical role in regulating the germline transcriptome, ensuring proper gene expression for the mitosis-to-meiosis transition.
• MTR4's function is vital for maintaining genomic integrity and reproductive success.