Single-cell Regulatory Occupancy Archive in Dementia

Database: Single-cell Regulatory Occupancy Archive in Dementia – scROAD

What We Can Do with scATAC-seq Data

scATAC-seq data enables us to explore chromatin accessibility at a single-cell level, allowing for the identification of regulatory elements that are active in specific cell types. This technique is particularly powerful for investigating transcription factor binding sites (TFBS) and understanding gene regulatory networks in the context of complex diseases like Alzheimer’s Disease (AD) and Pick’s Disease (PiD).

Our comprehensive approach integrates genomic data from various sources, including GWAS fine-mapping, single-nucleus ATAC-seq (snATAC-seq), and single-nucleus RNA-seq (snRNA-seq), to uncover the genetic underpinnings of neurodegenerative diseases. By mapping disease-associated loci to specific cell types, we can investigate the functional alterations due to genetic variants in disease contexts, such as AD and PiD.

I developed a wrapper package, scCis-TF, designed to streamline the extraction of information from single-cell data generated by CellRanger ATAC, Seurat, and Signac into Cicero and TOBIAS for comprehensive analysis. We performed single-cell co-accessibility analyses using Cicero to construct putative cis-regulatory enhancer-promoter links. Additionally, with the help of the TOBIAS package, we further explored transcription factor (TF) binding occupancy in ATAC-seq. This analysis allows us to detect differences in TF binding between disease and control samples, providing insights into how regulatory mechanisms are altered in specific cell types.

By integrating TF binding data with co-accessibility analyses to create this scCis-TF interactive database, users can easily explore transcription factor binding activity and their implications in disease, providing a valuable resource for understanding gene regulation in neurodegeneration.

About the Database

This database (Shi et al., 2024) offers comprehensive information on single-cell cCRE transcription factor occupancy data generated from snATAC-seq analysis of human postmortem prefrontal cortex (PFC) tissue. The data specifically focuses on Alzheimer’s Disease and Pick’s Disease. For a more in-depth understanding of the database’s purpose and contents, please refer to the following publication. If you have any further questions, feel free to contact the principal investigator.

GWAS snATAC scCis-TF occupancy plot showcasing key transcription factor binding sites

Running the code for Single-cell Regulatory Occupancy Analysis

Code will be updated here soon

The study of neurodegenerative diseases, particularly tauopathies like Pick’s disease (PiD) and Alzheimer’s disease (AD), offers insights into the underlying regulatory mechanisms. By investigating epigenomic variations in these conditions, we identified critical regulatory changes driving disease progression, revealing potential therapeutic targets. Our comparative analyses uncovered disease-enriched non-coding regions and genome-wide transcription factor (TF) binding differences, linking them to target genes. Notably, we identified a distal human-gained enhancer (HGE) associated with E3 ubiquitin ligase (UBE3A), highlighting disease-specific regulatory alterations. Additionally, fine-mapping of AD risk genes uncovered loci enriched in microglial enhancers and accessible in other cell types. Shared and distinct TF binding patterns were observed in neurons and glial cells across PiD and AD. We validated our findings using CRISPR to excise a predicted enhancer region in UBE3A and developed an interactive database (http://swaruplab.bio.uci.edu/scROAD) to visualize predicted single-cell TF occupancy and regulatory networks.

What We Can Do with scATAC-seq Data

About the Database

Running the code for Single-cell Regulatory Occupancy Analysis

References

2024