H3 acetylation selectively promotes basal progenitor proliferation and neocortex expansion

Area of Science:

• Neuroscience
• Developmental Biology
• Epigenetics

Background:

• Human cognitive capacity is linked to neocortex size, which expanded during evolution.
• Basal progenitors (BPs) in the mammalian cortex exhibit enhanced proliferation, contributing to cortical expansion.
• Epigenetic alterations in BPs are hypothesized to underlie species-specific differences in cortical development.

Purpose of the Study:

• To investigate how the epigenome of basal progenitors (BPs) differs across species.
• To identify key epigenetic mechanisms regulating basal intermediate progenitor (bIP) amplification and neocortical expansion.

Main Methods:

• Epigenetic profiling of sorted basal progenitors (BPs) from murine and human developing cortices.
• Analysis of histone H3 acetylation patterns, specifically H3K9ac.
• Assessment of gene expression changes, focusing on the *Trnp1* gene.

Main Results:

• Histone H3 lysine 9 acetylation (H3K9ac) is significantly lower in murine bIPs compared to human bIPs.
• Elevated H3K9ac in bIPs promotes their proliferation, leading to increased neocortical size and folding.
• H3K9ac upregulates the expression of the evolutionarily regulated gene *Trnp1* in the developing cortex, driving bIP amplification.

Conclusions:

• Histone H3 acetylation, particularly H3K9ac, is a critical epigenetic regulator of basal progenitor amplification.
• Differences in H3K9ac levels between species contribute to variations in neocortical architecture and size.
• This study uncovers a novel epigenetic mechanism controlling the evolution of cortical complexity.