RefTM: reference-guided topic modeling of single-cell chromatin accessibility data.

Single-cell analysis is a valuable approach for dissecting the cellular heterogeneity, and single-cell chromatin accessibility sequencing (scCAS) can profile the epigenetic landscapes for thousands of individual cells. It is challenging to analyze scCAS data, because of its high dimensionality and a higher degree of sparsity compared with scRNA-seq data. Topic modeling in single-cell data analysis can lead to robust identification of the cell types and it can provide insight into the regulatory mechanisms. Reference-guided approach may facilitate the analysis of scCAS data by utilizing the information in existing datasets. We present RefTM (Reference-guided Topic Modeling of single-cell chromatin accessibility data), which not only utilizes the information in existing bulk chromatin accessibility and annotated scCAS data, but also takes advantage of topic models for single-cell data analysis. RefTM simultaneously models: (1) the shared biological variation among reference data and the target scCAS data; (2) the unique biological variation in scCAS data; (3) other variations from known covariates in scCAS data.