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Chromatin Structure Regulates pre-mRNA Processing

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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.

Overview

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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.

Transcript

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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.

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Chromatin Structure

Pre mRNA Processing

Gene Transcription

Nucleosome Positioning

Histone Modifications

RNA Polymerase Activity

Promoter Element

Transcriptional Start Site

Elongation Factors

Chromatin Remodeling Complex

5 Capping Enzymes

Spliceosome Components