RNA-binding proteins connect Exon usage to the chromatin

Area of Science:

• Genomics
• Epigenetics
• Molecular Biology

Background:

• Histone modifications are implicated in regulating gene expression, including alternative splicing.
• Understanding the interplay between epigenomic marks and splicing outcomes is crucial for deciphering gene regulation.

Purpose of the Study:

• To investigate the connection between the epigenome and transcriptome in the context of alternative splicing in embryonic cell lines.
• To identify RNA-binding proteins (RBPs) that mediate the influence of epigenetic marks on differential exon inclusion.

Main Methods:

• Utilized rMATS and MANorm to analyze differential exon inclusion and epigenetic signal enrichment.
• Trained binary classifiers using RNA-binding protein binding affinities to link chromatin modifications with splicing.
• Analyzed eCLIP data to validate predicted RBPs.

Main Results:

• Identified two classes of alternative exons: those associated with specific histone marks (H3K27ac, H3K27me3, H3K36me3, H3K9me3, H3K4me3) and those without.
• Predicted a set of RBPs whose binding associates local chromatin marks with differential exon inclusion.
• TIA1 and U2AF2 were supported as potential episplicing RBPs based on eCLIP data.

Conclusions:

• Epigenetic signatures on exons play a role in regulating alternative splicing outcomes.
• Sequence signals at exon-intron boundaries, influenced by RBPs and chromatin modifications, likely drive differential splicing.
• The findings provide insights into the mechanisms of episplicing and its regulation by histone marks.