Quantifying cell-state densities in single-cell phenotypic landscapes using Mellon

Cell-state density characterizes the distribution of cells along phenotypic landscapes and is crucial for unraveling the mechanisms that drive diverse biological processes. Here, we present Mellon, an algorithm for estimation of cell-state densities from high-dimensional representations of single-cell data. We demonstrate Mellon’s efficacy by dissecting the density landscape of differentiating systems, revealing a consistent pattern of high-density regions corresponding to major cell types intertwined with low-density, rare transitory states. We present evidence implicating enhancer priming and the activation of master regulators in emergence of these transitory states. Mellon offers the flexibility to perform temporal interpolation of time-series data, providing a detailed view of cell-state dynamics during developmental processes. Mellon facilitates density estimation across various single-cell data modalities, scaling linearly with the number of cells. Our work underscores the importance of cell-state density in understanding the differentiation processes, and the potential of Mellon to provide insights into mechanisms guiding biological trajectories.