Low Input Asay for Transposase-Accessible Chromatin Identifies Epigenetic Signatures of Liver Group 1 Innate Lymphoid Cells

Epigenetic regulation is fundamental to the development, activation, and memory formation of Group 1 innate lymphoid cells (ILCs), including NK cells and ILC1s. Studying chromatin accessibility in these cells, especially from tissues, is limited by low cell numbers. Here, we present a robust, low-input bulk ATAC-seq protocol optimized for primary NK cells and ILC1s. Our improved protocol achieves high-quality libraries with as few as 5,000 cells. Applying this protocol to liver-derived NK cells and ILC1s, we identify over 30,000 differentially accessible regions, reflecting distinct epigenetic regulation. Our findings reveal key transcription factor motifs and confirm known gene accessibility patterns, highlighting functional divergence between these cell types. This accessible protocol enables reliable epigenetic profiling of rare ILC populations, improving the study of tissue-resident immunity. Overall design: ATAC-seq profiling of primary Group 1 ILCs from wild-type C57Bl/6J mouse liver.