Single-nucleus multiome analysis in the human prefrontal cortex identifies gene expression and cis-regulatory...

Area of Science:

• Neuroscience
• Genomics
• Molecular Biology

Background:

• Aging involves molecular changes in the brain, but these are not fully understood.
• Existing research has gaps in characterizing age-associated molecular alterations at a cellular level.

Purpose of the Study:

• To comprehensively profile age-associated molecular and epigenomic changes across diverse human brain cell types.
• To identify cell-type-specific regulatory networks and cis-regulatory elements influenced by the aging process.

Main Methods:

• Generated single-nucleus multiome ATAC and gene expression (GEX) profiles from 357 human brain samples across a wide age range (15-100 years).
• Analyzed paired transcriptomic and epigenomic data from over 1.5 million cells, classified into seven major cell types.
• Correlated open chromatin regions with transcription factor expression to identify age-associated regulatory networks and linked peaks/genes.

Main Results:

• Identified cell-type-specific molecular features associated with brain aging.
• Cataloged putative cis-regulatory elements by cell type, linking open chromatin regions to gene expression.
• Revealed age-associated regulatory networks and co-accessibility patterns within distinct brain cell populations.

Conclusions:

• The generated multiomic dataset provides a valuable resource for understanding brain aging.
• Characterized transcriptional regulation by cell type, offering insights into how aging influences and is influenced by distinct cellular profiles.
• Generated hypotheses regarding the role of cell-type-specific regulatory elements in aging and brain disease.