Eukaryotic gene expression involves tight coordination between transcription and 
pre-mRNA splicing; however, factors responsible for this coordination remain 
incompletely defined. Here, we explored the genetic, functional, and biochemical 
interactions of a likely coordinator, Npl3, an SR-like protein in Saccharomyces 
cerevisiae that we recently showed is required for efficient co-transcriptional 
recruitment of the splicing machinery. We surveyed the NPL3 genetic interaction 
space and observed a significant enrichment for genes involved in histone 
modification and chromatin remodeling. Specifically, we found that Npl3 
genetically interacts with both Bre1, which mono-ubiquitinates histone H2B as 
part of the RAD6 Complex, and Ubp8, the de-ubiquitinase of the SAGA Complex. In 
support of these genetic data, we show that Bre1 physically interacts with Npl3 
in an RNA-independent manner. Furthermore, using a genome-wide splicing 
microarray, we found that the known splicing defect of a strain lacking Npl3 is 
exacerbated by deletion of BRE1 or UBP8, a phenomenon phenocopied by a point 
mutation in H2B that abrogates ubiquitination. Intriguingly, even in the 
presence of wild-type NPL3, deletion of BRE1 exhibits a mild splicing defect and 
elicits a growth defect in combination with deletions of early and late splicing 
factors. Taken together, our data reveal a connection between Npl3 and an 
extensive array of chromatin factors and describe an unanticipated functional 
link between histone H2B ubiquitination and pre-mRNA splicing.