First Exon Length Controls Active Chromatin Signatures and Transcription

Here, we explore the role of splicing in transcription, employing both genome-wide analysis of human ChIP-seq data and experimental manipulation of exon-intron organization in transgenic cell lines. We show that the activating histone modifications H3K4me3 and H3K9ac map specifically to first exon-intron boundaries. This is surprising, because these marks help recruit general transcription factors (GTFs) to promoters. In genes with long first exons, promoter-proximal levels of H3K4me3 and H3K9ac are greatly reduced; consequently, GTFs and RNA polymerase II are low at transcription start sites (TSSs) and exhibit a second, promoter-distal peak from which transcription also initiates. In contrast, short first exons lead to increased H3K4me3 and H3K9ac at promoters, higher expression levels, accuracy in TSS usage, and a lower frequency of antisense transcription. Therefore, first exon length is predictive for gene activity. Finally, splicing inhibition and intron deletion reduce H3K4me3 levels and transcriptional output. Thus, gene architecture and splicing determines transcription quantity and quality as well as chromatin signatures. [Display omitted] ► First exon length determines H3K4me3 profiles ► Promoter-proximal H3K4me3 profiles are splicing-dependent ► Short first exons act as transcriptional enhancers Why do introns correlate with transcriptional activity? Here, by combining genome-wide approaches and genetic engineering, Neugebauer and colleagues show that splicing contributes to transcriptional output. The data show that short first exons act as transcriptional enhancers, which recruit transcriptional machinery to gene starts. Thus, gene architectures most likely evolved to exploit this feature. Transcriptional enhancement appears to rely on the splicing-dependent positioning of the well-characterized activating histone mark H3K4me3, suggesting mechanistic links between splicing and transcription.