A crucial challenge is to extend reference-mapping to additional molecular modalities, including single-cell measurements of chromatin accessibility (e.g. scATAC-seq13,14), DNA methylation (scBS-seq15), histone modifications (scCUT&Tag16,17), and protein levels (CyTOF18), each of which measures a different set of features than scRNA-seq. The lack of transcriptome-wide measurements creates challenges for unsupervised annotation. Ideally, datasets from different modalities could be mapped onto scRNA-seq references, ensuring that established cell labels and ontologies would be preserved. We and others have proposed methods to map datasets across modalities19-21, but these make strict biological assumptions (for example, that accessible chromatin is associated with active transcription) that may not always hold true, particularly when analyzing cellular transitions or developmental trajectories22.
