UCLA

Despite its relatively streamlined genome, there are important examples of regulated RNA splicing in Saccharomyces cerevisiae. Here we show crucial roles for the chromatin remodeling complex SWI/SNF in splicing regulation in response to environmental changes. Nutrient-dependent downregulation of Snf2, the ATPase subunit of SWI/SNF, regulates downregulation of ribosomal protein genes (RPGs). RPGs are intron-enriched, and are highly transcribed. We show that their downregulation causes spliceosome redistribution from this abundant class of intron-containing RNAs to transcripts containing non-canonical splice-signals, which otherwise have poor affinity for the spliceosome.

Meiosis in S. cerevisiae is a response to prolonged starvation, involving regulated transcription and splicing of meiosis-specific transcripts. Splicing of a subset of these relies upon the meiosis-specific splicing activator Mer1. We find that SWI/SNF affects meiotic splicing in multiple ways. First, meiosis-specific downregulation of Snf2 leads to RPG downregulation and spliceosome redistribution to Mer1-regulated transcripts. Secondly, Mer1 expression is SWI/SNF dependent—Snf2 is poised at the MER1 promoter, and timing of Snf2 downregulation in relation to acetylation states of both itself and its target genomic loci allows coordination between these mechanisms. Hence, the SWI/SNF complex directs regulated meiotic splicing in S. cerevisiae. Furthermore, Snf2 itself is subject to precise regulation in response to cellular needs via several novel modes of RNA processing and regulation, as well as control of protein acetylation and turnover. This multi-level coordinated regulation orchestrates activity and targets of splicing programs as a cellular adaptive strategy in response to environmental stresses.

We also report roles for the SWI/SNF complex in respiration, partially via splicing regulation. Nutrient-dependent decrease in Snf2 leads to increase in PTC7 splicing, due to RPG downregulation and spliceosome redistribution. The spliced PTC7 transcript encodes a mitochondrial phosphatase regulator of Coenzyme Q6 (CoQ6) biosynthesis, a mitochondrial redox-active lipid essential for respiration, and increased PTC7 splicing increases CoQ6 levels. Contrastingly, the nonspliced PTC7 isoform encodes a protein repressing CoQ6 biosynthesis via as-yet-unknown mechanisms. These findings establish a novel role for SWI/SNF in the transition of yeast cells from fermentative to respiratory metabolism. Overall, the SWI/SNF complex regulates cellular stress responses by redirecting energy from translation to specialized splicing programs.