Asynchronous microexon splicing of LSD1 and PHF21A during neurodevelopment

Area of Science:

• Neuroscience
• Molecular Biology
• Epigenetics

Background:

• Lysine-specific demethylase 1 (LSD1) and PHF21A are crucial for neuronal function.
• Both proteins undergo neuron-specific microexon splicing, impacting their activity and interactions.
• The temporal dynamics of these splicing events during development were previously unknown.

Approach:

• Investigated the temporal expression of LSD1 and PHF21A splicing isoforms during human neuron differentiation and mouse brain development.
• Analyzed the impact of asynchronous splicing on the LSD1-PHF21A complex activity and its interaction with other proteins.
• Utilized techniques to study protein-protein interactions and gene regulation in neuronal contexts.

Key Points:

• Neuronal PHF21A isoform expression precedes neuronal LSD1 isoform expression during development.
• Asynchronous splicing leads to stepwise deactivation of the H3K4 demethylation activity of the LSD1-PHF21A complex.
• The PHF21A microexon is dispensable for neuron-specific protein-protein interactions, which are mediated by the broader neuronal proteomic environment.

Conclusions:

• The LSD1-PHF21A complex becomes enzymatically inactive in neurons due to asynchronous microexon splicing.
• Interactions with neuron-specific partners like MYT1 factors and VIRMA occur independently of the PHF21A microexon.
• The inactive LSD1-PHF21A complex may possess novel gene-regulatory functions in neurons, distinct from its demethylase activity.