Transposition of native chromatin for multimodal regulatory analysis and personal epigenomics

Several limitations of current epigenomic technology preclude their use in many experimental and clinical settings. Here we describe Assay for Transposase Accessible Chromatin using sequencing (ATAC-seq)— based on direct in vitro transposition of sequencing adapters into native chromatin – as a rapid and sensitive method for integrative epigenomic analysis. ATAC-seq captures open chromatin sites using a simple 2-step protocol from 500 to 50,000 cells, and reveals the interplay between genomic locations of open chromatin, DNA binding proteins, individual nucleosomes, and higher-order compaction at regulatory regions with nucleotide resolution. We discover classes of DNA binding factor that strictly avoid, can tolerate, or tend to overlap with nucleosomes. Using ATAC-seq, we measured and interpreted the serial daily epigenomes of resting human T cells from a proband via standard blood draws, demonstrating the feasibility of reading personal epigenomes in clinical timescales for monitoring health and disease.