Manifold alignment reveals correspondence between single cell transcriptome and epigenome dynamics

Single cell genomic techniques promise to yield key insights into the dynamic interplay between gene expression and epigenetic modification. However, the experimental difficulty of performing multiple measurements on the same cell currently limits efforts to combine multiple genomic data sets into a united picture of single cell variation. We show that it is possible to construct cell trajectories, reflecting the changes that occur in a sequential biological process, from single cell ATAC-seq, bisulfite sequencing, and ChIP-seq data. In addition, we present an approach called MATCHER that computationally circumvents the experimental difficulties inherent in performing multiple genomic measurements on a single cell by inferring correspondence between single cell transcriptomic and epigenetic measurements performed on different cells of the same type. MATCHER works by first learning a separate manifold for the trajectory of each kind of genomic data, then aligning the manifolds to infer a shared trajectory in which cells measured using different techniques are directly comparable. Using scM&T-seq data, we confirm that MATCHER accurately predicts true single cell correlations between DNA methylation and gene expression without using known cell correspondence information. We also used MATCHER to infer correlations among gene expression, chromatin accessibility, and histone modifications in single mouse embryonic stem cells. These results reveal the dynamic interplay between epigenetic changes and gene expression underlying the transition from pluripotency to differentiation priming. Our work is a first step toward a united picture of heterogeneous transcriptomic and epigenetic states in single cells.