Inference of emergent spatio-temporal processes from single-cell sequencing reveals feedback between de novo DNA methylation and chromatin condensates [Bisulfite-Seq 2]

Biological function relies, however, on emergent processes in the three-dimensional space of the nucleus, such as droplet formation through phase separation. Here, we use single-cell multi-omics sequencing to develop a theoretical framework to rigorously map epigenome profiling along the DNA sequence onto a description of the emergent spatial dynamics in the nucleus.

Drawing on scNMT-seq multi-omics sequencing in vitro and in vivo we exemplify our approach in the context of exit from pluripotency and global de novo methylation of the genome. We show how DNA methylation patterns of the embryonic genome are established through the interplay between spatially correlated DNA methylation and topological changes to the DNA. This feedback leads to the predicted formation of 30-40nm sized condensates of methylated DNA and determines genome-scale DNA methylation rates.