Chen, S.; Regev, A.; Condon, A.; Ding, J.

Single-cell RNA-seq data have provided new insights into intracellular and intercellular processes. Because multiple processes are active in each cell simultaneously, such as its cell type program, differentiation, the cell cycle, and environmental responses, their respective signals can confound one another, requiring methods that can separate and filter different complex biological signals. Each such signal is based on different gene activities and can define different relationships between cells. However, existing methods often focus on a single process or rely on overly restrictive assumptions, thus removing, rather than disentangling biological signals. Here, we develop CellUntangler, a deep generative model that embeds cells into a flexible latent space composed of multiple subspaces, each designed with an appropriate geometry to capture a distinct signal. We apply CellUntangler to datasets containing only cycling cells and both cycling and non-cycling cells, generating embeddings in which the cell cycle signal is disentangled from non-cell cycle specific signals, such as cell type or differentiation trajectory. We demonstrate CellUntangler\'s extensibility by using it to capture and separate spatial from non-spatial signals. With CellUntangler, we can obtain latent embeddings that capture various biological signals and perform enhancement or filtering at the gene expression level for downstream analyses.