Background. Pre-mRNA splicing occurs mainly co-transcriptionally, and both nucleosome density and histone modifications have been proposed to play a role in splice site recognition and regulation. However, the extent and mechanisms behind this interplay remain poorly understood./nResults. We use transcriptomic and epigenomic data generated by the ENCODE project to investigate the association between chromatin structure and alternative splicing. We find a strong and significant positive association between H3K9ac, H3K27ac, H3K4me3, epigenetic marks characteristic of active promoters, and exon inclusion in a small but well-defined class of exons, representing approximately 4 % of all regulated exons. These exons are systematically maintained at comparatively low levels of inclusion across cell types, but their inclusion is significantly enhanced in particular cell types when in physical proximity to active promoters./nConclusion. Histone modifications and other chromatin features that activate transcription can be co-opted to participate in the regulation of the splicing of exons that are in physical proximity to promoter regions.

We acknowledge support of the Spanish Ministry of Economy and Competitiveness, ‘Centro de Excelencia Severo Ochoa 2013-2017’, SEV-2012-0208. JC was supported by a SFRH/BD/33535/2008 from the Portuguese Foundation to Science and Technology. CI was supported by a La Caixa predoctoral fellowship. Work in JV’s lab was supported by Fundación Botín, by Banco de Santander through its Santander Universities Global Division and by Consolider RNAREG, MINECO, and AGAUR. We thank Anshul Kundaje, Ben Brown, Michael Snyder, Thomas Gingeras, and Alberto Kornblihtt for useful discussions and access to data, and Romina Garrido for administrative assistance.