Epigenomic profiling of human tissues at single-cell resolution

Abstract

Traditional methods for profiling DNA-protein binding interactions have been limited by low signalto-noise, false positives, and high costs. To overcome these barriers we developed a simple assay, Cleavage Under Targets & Tagmentation (CUT&Tag), that leverages a transposon based fusion enzyme to map in situ DNA-protein interactions in small samples of cells at high resolution. We then automated CUT&Tag to generate hundreds of chromatin profiles for a multitude of histone modifications across different diseases. Furthermore, we are able to model their cell-type specific gene expression by integrating the data across multiple histone modifications. CUT&Tag is characterized by an exceptionally high signal-to-noise ratio and we reasoned that the method could be used to resolve single-cell chromatin profiles. As a proof-of-concept we demonstrated that single-cell CUT&Tag resolves both active and repressive chromatin marks in cell lines. We then leveraged single-cell CUT&Tag to profile thousands of single cells to uncover the heterogeneity in stem cell development, primary liquid, and solid tumors pre- and post-treatment. Our work is part of a large-scale effort to build a comprehensive map of all cell types to better understand human health and improve disease diagnosis and treatment.