Abstract
Alternative splicing is well understood to enhance proteome diversity as cells respond to stimuli. However, mechanistic understanding for how the spliceosome processes precursor messenger RNA (mRNA) transcripts to achieve template diversification is incomplete. We use recently developed enzymatic inhibitors of protein arginine methyltransferase 5 (PRMT5) and human naive T lymphocyte activation as a model system to uncover a precise set of mRNA transcripts that require symmetric arginine dimethylation. This methylation-dependent splicing selectivity is associated with a limited set of signaling pathways that are affected when PRMT5 is inhibited. Specifically, we identify a conserved role for symmetric arginine dimethylation in the induction of antiviral type I and type III interferon signaling following Tcell receptor and pattern recognition receptor stimulation in human T lymphocytes and undifferentiated human THP-1 monocytes. Altogether, these findings reveal a mechanism by which cells may be enabled toprecisely modulate transcript heterogeneity to orchestrate specific functional outcomes.
Highlights
Alternative splicing is a mechanism used by eukaryotic cells to expand a relatively small number of productive DNA coding sequences into a diverse array of processed messenger RNA transcripts
Symmetric Arginine Dimethylation Is Selectively Required for Pre-messenger RNA (mRNA) Splicing To study the role of symmetric arginine dimethylation in premRNA splicing, we first defined a comprehensive signature of alternative splicing that occurs during human naive T lymphocyte activation
The RNA splicing analysis tool rMATS (Shen et al, 2014) was used to identify naive T lymphocyte activation-dependent splicing alterations that are shared between activated naive CD4+ and activated naive CD8+ T cells following stimulation
Summary
Alternative splicing is a mechanism used by eukaryotic cells to expand a relatively small number of productive DNA coding sequences into a diverse array of processed messenger RNA (mRNA) transcripts. In humans, >95% of multi-exonic precursor mRNA (pre-mRNA) transcripts undergo alternative splicing, and cells must coordinate a complex network of splicing mechanisms to process pre-mRNA into the multitude of transcript variants that dictate cellular function and identity (Nilsen and Graveley, 2010). One such mechanism that cells exploit is symmetric arginine dimethylation of three core spliceosome components: SmB/B0, SmD1, and SmD3. The full extent of methylation-dependent splicing regulation is unknown
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