In eukaryotic cells, nascent mRNA transcripts need to undergo many post-transcriptional modifications to reach the cell cytoplasm and translate into functional proteins. For a long time, transcription and pre-mRNA processing were considered two independent events that occur sequentially in the cell. However, it has now been well established that transcription and pre-mRNA processing are two simultaneous processes that are precisely regulated inside the cell.
The chromatin structure, especially the nucleosome positioning and histone modifications on the gene, can profoundly control the rate of RNA polymerase activity and pre-mRNA processing at the transcription site. Specific histone modifications on exon-specific nucleosomes help recruit splicing factors to the splice sites and play an active role in exon selection during splicing. For example, histone deacetylation leads to a tight chromatin structure. This slows down the RNA polymerase activity giving enough time to recruit splicing factors even at weak splice sites, leading to the inclusion of alternative exons in the mature mRNA. On the contrary, histone acetylation results in a more open chromatin structure that allows a faster RNA polymerase activity and recruitment of splicing factors only to the strong splice sites, resulting in the exclusion of alternative exons. Therefore, chromatin structure plays an important role in constitutive as well as alternative splicing of the pre-mRNA and regulates the gene expression patterns in the cell.
Another example of regulation of RNA splicing by the chromatin structure is the enriched trimethylation of H3 histone lysine 36 on the nucleosomes, which helps to recruit splicing factors to the splicing site. Mutations in the methylation process of H3 histone can disrupt the splicing process and result in intron retention in the mature mRNA.
Overall, the regulation of pre-mRNA processing, especially splicing, results in creating a diverse pool of mRNA transcripts and hence, enormous protein diversity from a finite set of genes.
