Gene expression is a tightly regulated process that involves properly synthesizing an RNA transcript from DNA, as well as RNA processing to correctly prepare it for proper translation into a protein. One key step in RNA processing is RNA splicing, the process by which non protein coding regions, known as introns, are removed from the RNA. It has been previously shown that splicing can occur co‐transcriptionally, and therefore there is the potential for coupling between transcription and RNA splicing. Mechanisms of coupling are currently being explored and one group of candidate proteins for coupling are histone modification enzymes and the histones that they modify. Chemical modifications to these histone proteins can alter histone association with the DNA, thereby regulating access of the transcription machinery to the DNA and impacting gene expression according to the needs of the cell. Therefore, these histone modification enzymes/modified histones are present at the right time and place to also regulate co‐transcriptional splicing. Here we tested the hypothesis that the NuA4 histone acetyltransferase and targeted acetylation of histone H4, which is known to alter chromatin structure and promote gene expression, is also important for regulating RNA splicing in Saccharomyces cerevisiae. NuA4, along with the chromatin remodeling enzyme Swr1, are also important for the insertion of and acetylation of the histone variant H2A.Z (a.k.a Htz1p), which is required for transcriptional activation. We investigated whether the NuA4 complex function and HTZ1 impacted splicing. Using genetic interaction studies, we revealed interactions between mutations that impact H4 acetylation/H2A.Z insertion and several splicing factor genes, implicating H4 acetylation and H2A.Z in RNA splicing. Furthermore, we show that point mutation of H4 or mutations that impair the function of the NuA4 complex both impact RNA splicing. We are now testing whether NuA4 or H4 acetylation are required for recruitment of splicing proteins to an RNA during transcription. Interestingly, our genetic interaction studies revealed a novel interaction between HTZ1 and genes involved in 3’ cleavage and polyadenylation machinery, which we are continuing to explore. Taken together our data support a role for the NuA4 enzyme, histone H4 acetylation and H2A.Z in RNA splicing, with potential connections to additional steps in RNA processing.

The NuA4 Acetyltransferase, Acetylation of Histone H4 and the H2A.Z Variant Histone are Required for Appropriate RNA Splicing in Saccharomyces cerevisiae

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The NuA4 Acetyltransferase, Acetylation of Histone H4 and the H2A.Z Variant Histone are Required for Appropriate RNA Splicing in Saccharomyces cerevisiae