The nuclear exosome co-factor MTR4 shapes the transcriptome for meiotic initiation (LACE-Seq)

Nuclear RNA decay has emerged as a mechanism for post-transcriptional gene regulation in cultured cells. However, whether this actually occurs in animals and is biologically relevant remains largely unexplored. Here, we demonstrate that MTR4, a central cofactor of the nuclear RNA exosome complex, is required for embryogenesis and spermatogenesis. Embryonic development of MTR4 knockout mice arrests at 6.5 days. Specific knock out of MTR4 in mouse advanced germ cells results in male infertility with a severe defect in meiotic initiation, with pre-meiotic germ cells accumulating a dysregulated transcriptome with mixed features of mitosis and meiosis. Interestingly, MTR4 pervasively binds to various types of RNAs but selectively degrades those exhibiting specific binding patterns. Moreover, polyadenylated retrotransposon RNAs are removed by the nuclear exosome, preventing their negative impacts on gene expression and potential mutagenic threat. Our work underscores the importance of nuclear RNA decay in regulating germline transcripts to ensure a gene expression program for the mitotic-to-meiotic transition. Overall design: To investigate which RNAs are bound by MTR4 in spermatogenesis, we sorted differented spermatogonia and conducted LACE-seq to detect the substrate of MTR4