Mechanism of robust epigenetic inheritance across ~50 cell divisions

Establish a definitive physical and biochemical mechanism by which epigenetic information—particularly H3K9me3-associated heterochromatin states—is robustly transferred through approximately 50 successive cell generations, given that chromatin conformations are highly dynamic and substantially reorganized during mitosis and that restoration of marks occurs on slow timescales.

Background

The paper argues that due to rapid chromatin dynamics and mitotic reorganization, epigenetic memory cannot plausibly be stored in static chromosome conformations, challenging prior models that rely on frozen structures.

Despite this, cells maintain heterochromatin states over many generations (on the order of the Hayflick limit), and the authors explicitly note that the field does not yet understand how such robust inheritance is achieved. The present work proposes PAC-based condensates as a plausible mechanism, but the general question remains explicitly stated as unresolved in the introduction.

References

This strongly suggests that the memory of the previous epigenetic state cannot be stored inside the chromosome conformation and that we do not understand yet why epigenetic information can be robustly transferred through 50 cell generations.

— A self-organised liquid reaction container for cellular memory (2412.15394 - Mukherjee et al., 19 Dec 2024) in Introduction, paragraph discussing chromatin dynamics and mitosis (near references [29], [30], [12])