Epigenetic regulation is essential for cell differentiation, lineage commitment, and the maintenance of cell identity. Epigenetic marks, which can be added or removed from chromatin, modulate chromatin packaging, thereby influencing access to genetic information. Frequently, cell identity can be associated with characteristic rugged epigenetic profiles with alternating levels of activating and repressive epigenetic modifications.

It has long been believed that the loss of cellular identity, a shared hallmark of cancer and ageing, is caused by the loss of genetic information due to the accumulation of mutations. However, recent evidence suggests that this loss is due to the erosion of epigenetic information. Specifically, high genomic instability can divert histone-modifying enzymes (HMEs) from histones to DNA repair sites. This relocation can disrupt the normal deposition and removal of epigenetic marks, leading to the flattening of rugged epigenetic profiles.

In this work, we present a model for epigenetic regulation in the context of 3D-folded chromatin. Our model offers a mechanistic explanation of how the relocation of HMEs under conditions of high DNA damage can erode rugged epigenetic patterns. By incorporating chromatin architecture into our framework, we also explore the robustness of various chromatin geometries in response to increased DNA breaks.