Inference of emergent spatio-temporal processes in single-cell genomics

During early development, when the first cell fate decisions are made, the genome undergoes large-scale changes in the primary layer of epigenetic modifications, DNA methylation. Combining novel methods from genomics with bioinformatics and non-equilibrium physics, we show that the establishment of DNA methylation is a collective phenomenon involving feedback ranging over large genomic domains. Surprisingly, we found that de-novo methylation follows universal dynamics that is self-similar in time and independent of the genomic context. We capture these findings in a mechanistic model of de-novo methylation. By mapping our model to a quantum field theory, we show how these epigenetic marks are established through the cooperative action of DNMT3 enzymes exhibiting long-range interactions and leading to genome-wide collective dynamics. Theoretical predictions are tested on extensive time-resolved sequencing data. Our work sheds new light on epigenetic mechanisms involved in cellular decision making, predicting the formation of condensates of methylation in the nucleus. It also highlights how mechanistic insights into the molecular processes governing cell-fate decisions can be gained by the combination of novel methods from genomics and non-equilibrium physics.