Chromatin Structure and RNA Splicing

In eukaryotes, the processing of pre-mRNA in the nucleus is tightly coupled to its transcription. 

As soon as RNA polymerase starts transcribing, the newly synthesized pre-mRNA is immediately bound by various factors to be processed into mature and functional mRNA. 

Therefore, the rate of gene transcription by the RNA polymerase directly affects the steps in pre-mRNA processing. 

One of the major factors that regulate the rate of RNA polymerase activity is the gene's chromatin structure, which includes nucleosome positioning and histone modifications on the DNA template. 

Nucleosomes are very strategically placed on certain regions of the DNA. They act as a barrier and temporarily pause the RNA polymerase activity on the DNA. 

For example, in most genes, a nucleosome is positioned after the promoter element. It compels the RNA polymerase to pause at the transcriptional start site, giving enough time for the assembly of elongation factors and chromatin remodeling complex that helps to create nucleosome free region on the template DNA. In the meantime, the cell can recruit 5' capping enzymes for the newly synthesized pre-mRNA. 

Nucleosome positioning is also favored on the exons compared to the introns. Specific histone modifications in these exon-specific nucleosomes help to recruit spliceosome components which can then be directly transferred to the RNA under synthesis. 

These histone modifications can also contribute to the exon selection on the emerging mRNA strand. Histone modifications on the nucleosomes can recruit different protein factors which can facilitate retention of constitutive or alternative exons in the mature mRNA strand. 

Finally, the replacement of normal histone H3 with its variants on the gene body can lead to defective recruitment of splicing factors, and enhance intron retention leading to degradation of resultant mRNA via the nonsense-mediated pathway or the introduction of mutations in the translated protein. 

Such abnormal splicing has been linked to many diseases, including neurodegenerative disorders and cancer.