Basic Science and Pathogenesis

Area of Science:

• Neuroscience
• Genomics
• Epigenetics

Background:

• Single-cell/nuclei multiome technologies enable simultaneous gene expression and chromatin accessibility profiling.
• This approach allows for cell type-specific investigation of regulatory mechanisms underlying Alzheimer's disease (AD).

Purpose of the Study:

• To investigate the regulatory underpinnings of AD/ADRD in the human cerebellum using single-nucleus multiome sequencing.
• To identify cell type-specific transcriptomic and epigenomic features associated with AD neuropathology in the cerebellum.

Main Methods:

• Conducted single-nucleus RNA sequencing (snRNA-seq) and single-nucleus assay for transposase-accessible chromatin sequencing (snATAC-seq) on postmortem human cerebellum and frontal cortex tissues.
• Utilized colocalization and fine-mapping to identify likely causal target genes in AD/ADRD cerebellum.
• Integrated snATAC-seq, genome-wide AD/ADRD loci, and Hi-C looping data for causal gene identification.

Main Results:

• Analyzed 103,861 nuclei from human cerebellum and frontal cortex, identifying disease-associated granule cell subpopulations in AD/ADRD.
• Discovered 431,834 significant linkages between gene expression and cell subtype-specific chromatin accessibility regions (cCREs).
• Identified key regulatory elements and transcription factors (e.g., RORA, ELF1) and two likely causal genes (SEZ6L2, KANSL1) in cerebellar cells.

Conclusions:

• This study provides a comprehensive, cell subtype-specific regulatory landscape of the human cerebellum in AD/ADRD.
• Offers novel genomic and epigenomic insights into AD/ADRD neuropathology and pathobiology.
• Highlights the potential for broader application in understanding other neurological disorders.