Histone Modifications Regulate Alternative Splicing Mechanism

The role of Histone Code in protein diversity seems to be very significant

https://www.frontiersin.org/articles/10.3389/fgene.2019.00122/full (18th Feb 2019)

Excerpt: "Alternative splicing is a process that can generate multiple mRNA isoforms from a single gene by splicing pre-mRNA molecules in different ways. As an important process of gene expression, alternative splicing ensures the diversity of gene expression products. It has been estimated that alternative splicing occurs in approximately 90% human genes. Alternative splicing is reported to closely correlate with apoptosis, embryonic development and even a series of diseases. Although great efforts have been made on studying alternative splicing, the mechanisms of cell type-specific and stage-specific alternative splicing are still unclear.

Recently, Shindo et al. (2013) found that the alternative splicing of the BIN1 gene in IMR90 cell was regulated by the cooperation of H3K36me3, H3K4me3, H2BK12ac, and H4K5ac. These results strongly indicate that histone modifications play important roles in RNA splicing regulation and are key clues for revealing the regulatory mechanism of alternative splicing.
Based on these experimental results, several computational methods have been proposed to predict the alternative exons in exon skipping event based on histone modifications. The pioneer work was proposed by Enroth et al. (2012), in which a rule-based model was developed to classify included and excluded exons based on histone modification combinations. Later on, based on Enroth et al.’s (2012) dataset, Chen et al. (2014) proposed a quadratic discriminant (QD) function method and obtained an accuracy of 68.5% for classifying the included and excluded exons in the exon skipping event. More recently, a random forest based method was developed for the same aim and obtained an accuracy of 72.91% in the 10-fold cross validation test (Chen et al., 2018b). These results strongly indicate that histone modifications play important roles in RNA splicing regulation and are key clues for revealing the regulatory mechanism of alternative splicing. These results indicate that we should find the novel splicing code from the epigenome information.


Based on the Pearson correlation coefficients, the casual relationships of histone modifications in the process of RNA splicing were deduced by constructing their Bayesian networks. The results indicate that the inclusion or exclusion of exons is influenced by combinatorial patterns of histone modifications. Some of the histone modifications contribute directly to RNA splicing (e.g., H3K36me3 and H3K79me1), while other histone modifications indirectly contribute to the RNA splicing.

The result that H3K36me3 and H3K79me1 can affect RNA splicing is consistent with previous studies which have demonstrated that H3K36me3 and H3K79me1 are enriched in included exons. The H3K36me3 can regulate alternative splicing by interacting with polypyrimidine tract-binding protein (PTB). By interacting with the Tudor domain of TP53BP1, the H3K79me1 was also reported to interact with that interacts with snRNP.

By relaxing the chromatin structure, the H3 and H4 acetylation were also reported to regulating inclusion or exclusion of the skipping exon. Besides the histone modifications located in exon regions, histone modifications located in intragenic regions can also influence RNA splicing by regulating RNAPII elongation rates, or by directly binding to splicing factors and hence mediating their binding to pre-mRNA."

My comment: Histone code is a complex database being able to store epigenetic information that strongly affects DNA transcription, pre-mRNA splicing and post-transcriptional modifications of mRNA. It's clear that the histone code regulates organismal characteristics. By using histone epigenetic markers cells are able to convert digital (marker) information to analog information. The histone code is an indication of Intelligent Code of life, complex biological information that is designed by our Creator. The histone code is maintained by writers, readers and erasers which points to Intelligent Design. However, there is no mechanism for evolution, because epigenetic mechanisms only regulate pre-existing biological information. Don't get lost.