Chromatin-mediated alternative splicing regulates cocaine-reward behavior

Area of Science:

• Neuroscience
• Molecular Biology
• Epigenetics

Background:

• Neuronal alternative splicing is crucial for brain function but not fully explained by spliceosome activity alone.
• The histone modification H3K36me3 is implicated as a potential regulator of activity-dependent alternative splicing.
• Cocaine self-administration induces significant changes in gene splicing within the brain.

Purpose of the Study:

• To investigate the direct role of H3K36me3 in activity-dependent alternative splicing in the brain.
• To determine if H3K36me3 directly influences splice factor expression or splicing events.
• To establish the causal link between H3K36me3, alternative splicing, and reward behavior.

Main Methods:

• Analyzed differential alternative splicing and H3K36me3 enrichment in mouse brains after cocaine self-administration.
• Utilized targeted epigenetic editing to manipulate H3K36me3 levels at specific gene loci.
• Focused on the Srsf11 gene, which exhibited both alternative splicing and H3K36me3 enrichment post-cocaine exposure.

Main Results:

• Cocaine self-administration led to widespread differential alternative splicing and H3K36me3 enrichment at these junctions.
• Targeted epigenetic editing of H3K36me3 at the Srsf11 gene directly induced its alternative splicing.
• This epigenetic modification also enhanced cocaine self-administration behavior in mice.

Conclusions:

• H3K36me3 plays a direct causal role in the alternative splicing of Srsf11.
• Epigenetic regulation of H3K36me3 is directly involved in modulating alternative splicing and reward-related behaviors, such as those influenced by cocaine.