Histone marks regulate the epithelial-to-mesenchymal transition via alternative splicing

Area of Science:

• Epigenetics
• Molecular Biology
• Cell Biology

Background:

• Histone modifications influence gene splicing outcomes.
• Evidence linking specific histone marks to cell-specific splicing changes is limited.
• Alternative splicing plays a role in cellular reprogramming and phenotype changes.

Purpose of the Study:

• To investigate the causal role of histone modifications in inducing cell-specific alternative splicing.
• To determine if altering histone marks can recapitulate aspects of epithelial-to-mesenchymal transition (EMT).
• To elucidate the mechanism by which histone marks regulate splicing during EMT.

Main Methods:

• Utilized CRISPR epigenome editing tools to precisely modify histone marks (H3K27ac, H3K27me3).
• Employed an epithelial-to-mesenchymal transition (EMT) cell reprogramming system.
• Analyzed splicing changes and their impact on cell motility and invasiveness.
• Investigated the recruitment of splicing regulator PTB.

Main Results:

• A single alteration in H3K27ac or H3K27me3 levels at an alternatively spliced exon was sufficient to induce splicing changes.
• These induced splicing changes recapitulated key EMT characteristics, including increased cell motility and invasiveness.
• The histone-mark-dependent splicing regulation was dynamic and mediated by direct recruitment of PTB.
• Demonstrated a direct link between specific histone marks and cell phenotype changes via alternative splicing.

Conclusions:

• H3K27ac and H3K27me3 marks are critical drivers of cell-specific alternative splicing.
• Epigenetic control of alternative splicing by histone marks can dynamically alter cell phenotype, as exemplified by EMT.
• Dynamic chromatin regulation provides a rapid mechanism to coordinate splicing responses to extracellular signals like EMT induction.