CoRE-ATAC: A deep learning model for the functional classification of regulatory elements from single cell and bulk...

Area of Science:

• Genomics and Bioinformatics
• Epigenetics
• Computational Biology

Background:

• Cis-regulatory elements (cis-REs) like promoters and enhancers control gene expression through transcription factor binding.
• Assays for Transposase-Accessible Chromatin using sequencing (ATAC-seq) identify active cis-REs but lack immediate functional insights.
• Inferring specific cis-RE functions from ATAC-seq data remains a challenge.

Purpose of the Study:

• To develop a deep learning framework (CoRE-ATAC) for inferring cis-RE functions by integrating DNA sequence and ATAC-seq data.
• To enhance the functional resolution of chromatin accessibility maps for disease-related regulatory disruptions.
• To enable the study of cis-RE functions in rare cell populations without cell sorting.

Main Methods:

• Developed CoRE-ATAC, a deep learning framework with novel encoders for integrating DNA sequence (reference/personal genotypes) and ATAC-seq data (cut sites, read pileups).
• Trained CoRE-ATAC on ATAC-seq data from 4 cell types (6 samples) and validated predictions on 7 cell types (40 samples).
• Utilized massively parallel reporter assays (MPRAs) to confirm enhancer predictions in human islet samples and analyzed aggregate single nucleus ATAC-seq (snATAC) data from immune cells.

Main Results:

• CoRE-ATAC accurately predicted known cis-RE functions across cell types not used in training (mean average precision = 0.80, mean F1 score = 0.70).
• Enhancer predictions in human islets correlated with genetically modulated activity, validated by MPRAs.
• Inferred cis-RE functions from snATAC data in blood immune cells aligned with known annotations, demonstrating efficacy for rare cell types.

Conclusions:

• CoRE-ATAC significantly increases the functional resolution of ATAC-seq maps, enabling detailed study of cis-REs.
• The framework effectively predicts cis-RE function, integrating genomic sequence and chromatin accessibility data.
• CoRE-ATAC provides a powerful tool for investigating regulatory mechanisms underlying diseases, particularly in rare or unsorted cell populations.