Long range chromatin organization

Splicing is a predominantly co-transcriptional process that has been shown to be tightly coupled to transcription. Chromatin structure is a key factor that mediates this functional coupling. In light of recent evidence that shows the importance of higher order chromatin organization in the coordination and regulation of gene expression, we discuss here the possible roles of long-range chromatin organization in splicing and alternative splicing regulation. Recent evidence indicates that premRNA splicing occurs co-transcriptionally, i.e., before RNA polymerase II (RNAP II) has reached the end of the gene and while the transcript is associated to chromatin. Co-transcriptional splicing seems to be prevalent for most introns and in those introns whose excision was demonstrated to take place post-transcriptionally, splice site commitment and spliceosome assembly on the pre-mRNA were shown to occur mostly co-transcriptionally. Multiple levels of alternative splicing regulation have been described. On the one hand, the presence and relative position of regulatory elements on the pre-mRNA determine the recruitment of splicing factors and spliceosome components, whose abundance, activity and intracellular localization are subjected to regulation. On the other hand, as a consequence of the spatio-temporal coordination, both transcription and splicing were shown to be functionally coupled. In one of the mechanisms, known as “recruitment coupling,” splicing factors can be recruited to splice sites by the transcription machinery, which may also affect alternative splicing outcomes through the differential recruitment of these factors to promoters and enhancers as well as by alternative promoter usage. Alternatively, in the mechanism known as “kinetic coupling,” RNAP II elongation rate was shown to regulate alternative splicing by modulating the relative timing by which splice sites and regulatory sequences are transcribed and thus exposed to splicing factor binding and spliceosome component assembly. RNAP II elongation rate can be regulated both by factors recruited at gene promoters or along gene bodies and by the chromatin configuration of the DNA template. This introduces chromatin structure as another regulatory layer of alternative splicing. Chromatin is a highly dynamic structure that serves as an active platform for protein recruitment through specific histone marks and DNA methylation. Similar to the behavior of several protein complexes involved in transcriptional activation or repression, splicing factors can also be recruited to chromatin by direct or indirect binding to specific histone marks. The elongation control of alternative splicing is also dependent on how tightly DNA is wrapped around nucleosomes together with the capacity of the transcribing machinery to overcome these nucleosomal physical barriers. DNA packed into chromatin is also specified by histone marks that elicit the recruitment of nonhistone proteins with enzymatic activity that further modify chromatin structure. All together, nucleosome positioning, histone marks that determine a more loosened or compact Long range chromatin organization