Low-input ATAC&mRNA-Seq: a simple and robust method for simultaneous dual-omics profiling with low cell number

Deciphering epigenetic regulation of gene expression requires measuring the epigenome and transcriptome jointly. However, multi-omics profiling remains challenging for low-input samples. Therefore, we developed low-input ATAC&mRNA-Seq, a simple and robust method for studying the role of chromatin structure in gene regulation in a single experiment with thousands of cells, to maximize insights from limited input material by obtaining ATAC-seq and mRNA-seq data simultaneously from the same cells with data quality comparable to conventional mono-omics assays. Remarkably, integrative data analysis revealed similar strong association between promoter accessibility and gene expression using the data of low-input ATAC&mRNA-Seq as using single-assayed data, underscoring the accuracy and reliability of our dual-omics assay to generate both data types simultaneously with just thousands of cells. We envision our method to be widely applied in many biological disciplines with limited materials. Overall design: Low-input ATAC&mRNA-Seq was performed on E14 mESCs with 5K, 10K, and 20K cells. Two independent experiments were carried out on different days to assess data reproducibility. To benchmark our method, Omni-ATAC-seq was also conducted with 5K, 10K, and 50K of E14 mESCs.