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

Nature Communications, 17 March, 2025, DOI：https://doi.org/10.1038/s41467-025-57898-0

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

Li Zhang, Jianshu Wang, Zhidong Tang, Zhen Lin, Ruibao Su, Naijing Hu, Yao Tang, Gaoxiang Ge, Jing Fan, Ming-Han Tong, Yuanchao Xue, Yu Zhou & Hong Cheng

Abstract

Nuclear RNA decay has emerged as a mechanism for post-transcriptional gene regulation in cultured cells. However, whether this process occurs in animals and holds biological relevance remains largely unexplored. Here, we demonstrate that MTR4, the central cofactor of the nuclear RNA exosome, is essential for embryogenesis and spermatogenesis. Embryonic development of Mtr4 knockout mice arrests at 6.5 day. Germ cell-specific knockout of Mtr4 results in male infertility with a specific and severe defect in meiotic initiation. During the pre-meiotic stage, MTR4/exosome represses meiotic genes, which are typically shorter in size and possess fewer introns, through RNA degradation. Concurrently, it ensures the expression of mitotic genes generally exhibiting the opposite features. Consistent with these regulation rules, mature replication-dependent histone mRNAs and polyadenylated retrotransposon RNAs were identified as MTR4/exosome targets in germ cells. In addition, MTR4 regulates alternative splicing of many meiotic genes. Together, our work underscores the importance of nuclear RNA degradation in regulating germline transcriptome, ensuring the appropriate gene expression program for the transition from mitosis to meiosis during spermatogenesis.

文章链接：https://www.nature.com/articles/s41467-025-57898-0