A Self‐Organized Liquid Reaction Container for Cellular Memory

How cells restore epigenetic information lost during replication is not known. This work proposes a mechanism based on the formation of biomolecular condensates. These condensates are induced by the chromosome itself and serve as reaction vessels for reconstructing missing epigenetic markers. The study is a proof of concept, demonstrating that epigenetic information can be reconstructed across 50 cell generations. Abstract Epigenetic inheritance during cell division is essential for preserving cell identity by stabilizing the overall chromatin organization. Heterochromatin, the condensed and transcriptionally silent fraction of chromatin, is marked by specific epigenetic modifications that are diluted during each cell division. Here, we build a physical model, based on the formation of a biomolecular condensate, a liquid ‘droplet’, that promotes the restoration of epigenetic marks associated with heterochromatin. Heterochromatin facilitates the droplet formation via polymer‐assisted condensation (PAC). The resulting condensate serves as a reaction chamber to reconstruct the lost epigenetic marks. We incorporate the enzymatic reactions into a particle‐based simulation and monitor the progress of the heterochromatic epigenetic markers through an in silico analogue of the cell cycle. We demonstrate that the proposed mechanism is robust and stabilizes the heterochromatin domains over many cell generations. This mechanism and variations thereof might be at work for other epigenetic marks as well. How cells restore epigenetic information lost during replication is not known. This work proposes a mechanism based on the formation of biomolecular condensates. These condensates are induced by the chromosome itself and serve as reaction vessels for reconstructing missing epigenetic markers. The study is a proof of concept, demonstrating that epigenetic information can be reconstructed across 50 cell generations. Abstract Epigenetic inheritance during cell division is essential for preserving cell identity by stabilizing the overall chromatin organization. Heterochromatin, the condensed and transcriptionally silent fraction of chromatin, is marked by specific epigenetic modifications that are diluted during each cell division. Here, we build a physical model, based on the formation of a biomolecular condensate, a liquid ‘droplet’, that promotes the restoration of epigenetic marks associated with heterochromatin. Heterochromatin facilitates the droplet formation via polymer-assisted condensation (PAC). The resulting condensate serves as a reaction chamber to reconstruct the lost epigenetic marks. We incorporate the enzymatic reactions into a particle-based simulation and monitor the progress of the heterochromatic epigenetic markers through an in silico analogue of the cell cycle. We demonstrate that the proposed mechanism is robust and stabilizes the heterochromatin domains over many cell generations. This mechanism and variations thereof might be at work for other epigenetic marks as well. Advanced Science, EarlyView.