easyPairedTag: A Comprehensive Pipeline for Paired-Tag Data Quality Control and Analysis

Paired-Tag is an ultra-high throughput single-cell method for simultaneous profiling of gene expression and histone modifications, enabling identification of cell-type-specific cis-regulatory elements and correlation of their chromatin states with the expression levels of putative target genes. However, the lack of an automated end-to-end pipeline has limited its application. Here, we present easyPairedTag, a Snakemake pipeline for Paired-Tag data processing and quality control. Key features include flexible configuration for diverse experimental setups, automated sub-library merging and sample demultiplexing, and comprehensive quality control metrics. When applied to published mouse brain datasets, easyPairedTag improves overlapping gene quantification via strand-specific analysis for precise cell clustering. In mouse hypothalamus datasets, easyPairedTag is compatible with the processing of paired-end sequencing data to detect histone modification peaks with higher sensitivity and specificity, facilitating the discovery of putitive cell-type-specific cis-regulatory elements.