A Physics-based Model Reveals Mechanisms of Epigenetic Memory

Abstract

Cell type and specific functional identity are defined by the epigenetic patterning of chemical modifications to DNA and chromatin that modulate the expression and silencing of specific genes. When a cell divides, histones containing important epigenetic marks are distributed between the two daughter strands leading to a temporary dilution of epigenetic information and cell identity. The daughter cells must therefore reestablish the parental epigenetic pattern before the next cell division to ensure future progeny can continue to carry out their cell-type specific functions. In this work, we present a physics-based model involving polymer looping, epigenetic modifying enzymes, and phase condensates that explains how cells restore H3K9me3 and H3K27me3 histone methylation patterning after cell division. We validate our model via genome-wide epigenetic time-course simulation and comparison to experimental epigenetic data from multiple donors, multiple cell types, and for multiple epigenetic marks. Finally, we use our model as a conceptual framework to understand four factor partial and full reprogramming as a rejuvenation strategy.