Multiomic single-cell profiling identifies critical regulators of postnatal brain

Area of Science:

• Neuroscience
• Genomics
• Developmental Biology

Background:

• Human brain development involves complex gene expression changes.
• Cell-type-specific cis-regulatory elements and 3D genome organization are crucial.
• Understanding postnatal brain development is essential for neurological health.

Purpose of the Study:

• To comprehensively profile gene expression and chromatin accessibility during postnatal human brain development.
• To construct gene regulatory networks and identify cell-type-specific regulators.
• To interpret genetic associations with brain disorders using developmental data.

Main Methods:

• Simultaneous single-nucleus RNA sequencing and ATAC sequencing of 101,924 nuclei.
• Analysis across four brain regions and five postnatal stages (infancy to adulthood).
• Integration with chromosome conformation capture data to build enhancer-based gene regulatory networks.

Main Results:

• Identified 2,318 cell-specific loci linked to 1,149 genes, explaining 41% of trait-associated loci.
• Discovered 55 genes influencing multiple brain disease phenotypes.
• Characterized distinct stages of postnatal oligodendrogenesis and their regulatory mechanisms.

Conclusions:

• Provides a valuable dataset for studying cell-type-specific gene regulation in the developing human brain.
• Offers novel insights into the genetic underpinnings of brain development and neurological disorders.
• Highlights the importance of dynamic gene regulation during postnatal development for brain health.