Design principles of 3D epigenetic memory systems

Spreading of epigenetic marks—chemical modifications placed along the genome—may contribute to the stability of mark patterns as cells grow and divide, a form of epigenetic memory. But in the simplest models of this mechanism, there is a basic instability—if mark spreading is strong enough to restore a partially erased pattern, marks also spread uncontrollably to the rest of the genome. We developed a simple model coupling the dynamics of marks with the phase separation of chromatin, which reveals that emergent 3D genome organization can stabilize an epigenetic memory, as long as (1) there is a large density difference between chromatin compartments, (2) modifying “reader-writer” enzymes spread marks in 3D, and critically, (3) these enzymes are limited in abundance relative to their substrates. Analogous to an associative memory that encodes memory in neuronal connectivity, mark patterns are encoded in a 3D network of chromosomal contacts. Our model provides a unified account of diverse experimental observations, and reveals a key role for intramolecular phase separation of chromatin in the maintenance of epigenetic memory.