A multi-layered integrative analysis reveals a cholesterol metabolic program in outer radial glia with implications...

Area of Science:

• Neuroscience
• Evolutionary Biology
• Genomics

Background:

• Understanding human brain evolution necessitates detailed knowledge of molecular and cellular mechanisms driving developmental trajectories.
• Functional dissection of these mechanisms at a fine-grained level presents significant challenges.

Purpose of the Study:

• To develop an integrative computational framework for analyzing gene expression dynamics during human cortical development.
• To reconstruct gene regulatory networks and identify species-specific regulatory variants.
• To investigate the evolutionary changes in metabolic pathways during recent human brain evolution.

Main Methods:

• Trajectory inference and gene regulatory network reconstruction using (pseudo)time-informed non-negative matrix factorization.
• Paleogenomic analysis to map regulatory variants in humans compared to related species.
• Analysis of neural stem cells from the developing human cortex.

Main Results:

• Identified cell type-specific regulation of gene expression programs during indirect neurogenesis.
• Uncovered a crucial role for a cholesterol metabolism program in outer radial glia, regulated by KLF6.
• Detected signals of selection around regulatory regions impacting GLI3 and KLF6, suggesting recent evolutionary changes.

Conclusions:

• The study provides evidence for significant alterations in metabolic pathways during recent human brain evolution.
• Highlights the importance of KLF6-regulated cholesterol programs in human cortical development.
• Suggests evolutionary pressures on regulatory regions controlling radial glial cell cycle and gene regulation.