Chromatin density and splicing destiny: on the cross-talk between chromatin structure and splicing

Abstract

How are short exonic sequences recognized within the vast intronic oceans in which they reside? Despite decades of research, this remains one of the most fundamental, yet enigmatic, questions in the field of pre-mRNA splicing research. For many years, studies aiming to shed light on this process were focused at the RNA level, characterizing the manner by which splicing factors and auxiliary proteins interact with splicing signals, thereby enabling, facilitating and regulating splicing. However, we increasingly understand that splicing is not an isolated process; rather it occurs co-transcriptionally and is presumably also regulated by transcription-related processes. In fact, studies by our group and others over the past year suggest that DNA structure in terms of nucleosome positioning and specific histone modifications, which have a well established role in transcription, may also have a role in splicing. In this review we discuss evidence for the coupling between transcription and splicing, focusing on recent findings suggesting a link between chromatin structure and splicing, and highlighting challenges this emerging field is facing.

Figure 1

Mechanisms through which nucleosomes may be linked with exon–intron architecture and splicing. (A) Nucleosomes may serve as ‘speed bumps' for RNAPII, slowing down transcription rates and affecting splicing through the kinetic coupling model. (B) Different histone modifications, as indicated by the different coloured diamonds over the nucleosomes, may serve as signals for RNAPII, with one histone modification (e.g., acetylation) increasing transcription rates and others slowing it down. (C) The CTD domain of RNAPII serves as a landing pad for splicing factors, which are recruited to the pre-mRNA upon transcription. In parallel, splicing factors directly binding to chromatin are recruited to the pre-mRNA. (D) The CTD domain of RNAPII serves as a landing pad for chromatin remodellers, which alter the chromatin conformation along the exons, and thereby recruit splicing factors to exonic regions. CR, chromatin remodeller; SF, splicing factor.