Single-cell spatial map of cis-regulatory elements for disease-related genes in the macaque cortex

Area of Science:

• Neuroscience
• Genomics
• Molecular Biology

Background:

• Primate brain transcriptomic diversity is known, but underlying gene regulatory mechanisms and disease links are unclear.
• Understanding gene regulation is crucial for deciphering brain function and neurological disease pathogenesis.

Purpose of the Study:

• To investigate gene regulatory mechanisms in the primate cortex using snATAC-seq.
• To identify cell-type-specific chromatin accessibility profiles and their relation to brain region hierarchy and disease.

Main Methods:

• Performed single-nucleus Assay for Transposase-Accessible Chromatin followed by sequencing (snATAC-seq) on ~1.6 million cells from 142 cortical regions of two cynomolgus monkeys.
• Integrated snATAC-seq data with spatial transcriptome data for comprehensive analysis.
• Conducted cross-species comparisons with human data.

Main Results:

• Identified distinct chromatin accessibility profiles (cis-regulatory elements - CREs) for various cortical cell types.
• Discovered laminar and regional preferences of CREs, dependent on cortical hierarchy.
• Revealed human/macaque-enriched neuronal subtypes and CREs associated with neurodevelopment and psychiatric disorders.
• Linked genetic risk variants for brain disorders to primate-biased CREs in specific neuronal types and microglia.

Conclusions:

• Provided a foundational dataset for understanding spatial gene regulation in the primate cortex.
• Highlighted the role of specific CREs in primate-specific neuronal diversity and disease susceptibility.
• Established a link between genetic risk factors, CREs, and specific cell types in brain disorders.