SON controls mouse early embryonic development by regulating RNA splicing and histone methylation

Thousands of genes are activated in late two-cell embryos, which means that numerous pre-mRNAs are generated during this time. These pre-mRNAs must be accurately spliced to ensure that the mature mRNAs are translated into functional proteins. However, little is known about the roles of pre-mRNA splicing and the cellular factors modulating pre-mRNA splicing during early embryonic development. Here, we report that downregulation of SON, a large Ser/Arg (SR)-related protein, reduced embryonic development and caused deficient blastomere cleavage. These embryonic developmental defects result from dysregulated nuclear speckle organization and pre-mRNA splicing of a set of cell cycle-related genes. Furthermore, SON downregulation disrupted the transcriptome (2128 upregulated and 1399 downregulated) in four-cell embryos. Increased H3K4me3, H3K9me3, and H3K27me3 levels were detected in four-cell embryos after SON downregulation. Taken together, these results demonstrate that accurate pre-mRNA splicing is essential for early embryonic development and that SON plays important roles in nuclear speckle organization, pre-mRNA splicing, transcriptome establishment, and histone methylation reprogramming during early embryonic development.