EpiCHAOS: a metric to quantify epigenomic heterogeneity in single-cell data

Abstract Epigenetic heterogeneity is a fundamental property of biological systems, and is recognized as a potential driver of tumor plasticity and therapy resistance. Single-cell epigenomics technologies have been widely employed to study epigenetic variation between – but not within – cellular clusters. We introduce epiCHAOS: a quantitative metric of cell-to-cell heterogeneity, applicable to any single-cell epigenomics data type. After validation in synthetic datasets, we applied epiCHAOS to investigate global and region-specific patterns of epigenetic heterogeneity across diverse biological systems. EpiCHAOS provides an excellent approximation of stemness and plasticity in development and malignancy, making it a valuable addition to single-cell cancer epigenomics analyses. Competing Interest Statement The authors have declared no competing interest. Footnotes Email addresses: katherine.kelly{at}dkfz.de, michael.scherer{at}dkfz.de, martina.braun{at}crg.eu, pavlo.lutsik{at}kuleuven.be, c.plass{at}dkfz.de Figure 1D added to assess the influence of sequencing depth on epiCHAOS score; Figure 3E added to test epiCHAOS in the context of aging; Supplementary figures added to assess the influence of clustering resolution on epiCHAOS; minor modifications to the text.