Single‐cell multi‐modal chromatin profiles revealing epigenetic regulations of cells in hepatocellular carcinoma

Abstract Background Various epigenetic regulations systematically govern gene expression in cells involving various biological processes. Dysregulation of the epigenome leads to aberrant transcriptional programs and subsequently results in diseases, such as cancer. Therefore, comprehensive profiling epigenomics is essential for exploring the mechanisms underlying gene expression regulation during development and disease. Methods In this study, we developed single‐cell chromatin proteins and accessibility tagmentation (scCPA‐Tag), a multi‐modal single‐cell epigenetic profile capturing technique based on barcoded Tn5 transposases and a droplet microfluidics platform. scCPA‐Tag enables the simultaneous capture of DNA profiles of histone modification and chromatin accessibility in the same cell. Results By applying scCPA‐Tag to K562 cells and a hepatocellular carcinoma (HCC) sample, we found that the silence of several chromatin‐accessible genes can be attributed to lysine‐27‐trimethylation of the histone H3 tail (H3K27me3) modification. We characterized the epigenetic features of the tumour cells and different immune cell types in the HCC tumour tissue by scCPA‐Tag. Besides, a tumour cell subtype (C2) with more aggressive features was identified and characterized by high chromatin accessibility and a lower abundance of H3K27me3 on tumour‐promoting genes. Conclusions Our multi‐modal scCPA‐Tag provides a comprehensive approach for exploring the epigenetic landscapes of heterogeneous cell types and revealing the mechanisms of gene expression regulation during developmental and pathological processes at the single‐cell level. Highlights scCPA‐Tag offers a highly efficient and high throughput technique to simultaneously profile histone modification and chromatin accessibility within a single cell. scCPA‐Tag enables to uncover multiple epigenetic modification features of cellular compositions within tumor tissues. scCPA‐Tag facilitates the exploration of the epigenetic landscapes of heterogeneous cell types and provides the mechanisms governing gene expression regulation.