Single-cell Multiome Analysis of Chromatin State and Transcriptome in the Human Basal Ganglia

Area of Science:

• Neuroscience
• Genomics
• Epigenetics

Background:

• The basal ganglia are crucial for motor control, emotion, and learning, but their cellular gene regulation is poorly understood.
• Dysfunction of the basal ganglia is implicated in numerous neurological and psychiatric disorders.
• Interpreting disease-associated non-coding variants requires detailed knowledge of gene regulation.

Purpose of the Study:

• To create the first single-cell multiome atlas of histone modifications and transcriptomes in the human basal ganglia.
• To identify cell-type-specific gene regulatory programs and transcription factor codes.
• To link non-coding variants to neuropsychiatric disorders and develop predictive models.

Main Methods:

• Single-cell multiome sequencing of transcriptomes and histone modifications across eight human basal ganglia regions.
• Integration with spatial transcriptomic MERFISH data for regional epigenomic analysis.
• Comparative analysis between human and mouse medium spiny neurons.
• Development of a deep learning model for gene regulation prediction.

Main Results:

• Characterization of active and repressive chromatin states at single-cell resolution.
• Discovery of cell-type-specific gene regulatory networks governed by homeobox transcription factors.
• Identification of regional heterogeneity in epigenomic landscapes.
• Uncovering conserved gene regulatory features in medium spiny neurons between humans and mice.

Conclusions:

• The atlas provides cell-type resolution of gene regulation in the human basal ganglia.
• A combinatorial homeobox transcription factor code defines basal ganglia neuron identity.
• Non-coding neuropsychiatric risk variants are linked to specific cell types and regulatory elements.
• A deep learning model can predict gene regulation and prioritize functional disease variants.