Biophysical model for joint analysis of chromatin and RNA sequencing data

The assay for transposase-accessible chromatin using sequencing (ATAC-seq) can be used to identify open chromatin regions, providing complementary information to RNA-seq which measures gene expression by sequencing. Single-cell multiome methods offer the possibility of measuring both modalities simultaneously in cells, raising the question of how to analyze them jointly, and also the extent to which the information they provide is better than unregistered data, where single-cell ATAC-seq and single-cell RNA-seq are performed on the same sample, but on different cells. We propose and motivate a biophysical model for chromatin dynamics and subsequent transcription that can be used to parametrize multiome data, and use it to assess the benefits of multiome data over unregistered single-cell RNA-seq and single-cell ATAC-seq. We also show that our model provides a biophysically grounded approach to the integration of chromatin accessibility data with other modalitie, and apply the model to single-cell ATAC-seq data.