Predicting transcription factor binding in single cells through deep learning

Characterizing genome-wide binding profiles of transcription factors (TFs) is essential for understanding biological processes. Although techniques have been developed to assess binding profiles within a population of cells, determining them at a single-cell level remains elusive. Here, we report scFAN (single-cell factor analysis network), a deep learning model that predicts genome-wide TF binding profiles in individual cells. scFAN is pretrained on genome-wide bulk assay for transposase-accessible chromatin sequencing (ATAC-seq), DNA sequence, and chromatin immunoprecipitation sequencing (ChIP-seq) data and uses single-cell ATAC-seq to predict TF binding in individual cells. We demonstrate the efficacy of scFAN by both studying sequence motifs enriched within predicted binding peaks and using predicted TFs for discovering cell types. We develop a new metric "TF activity score" to characterize each cell and show that activity scores can reliably capture cell identities. scFAN allows us to discover and study cellular identities and heterogeneity based on chromatin accessibility profiles.