Preprint models the timing window for partial cellular reprogramming

Preprint models the timing window for partial cellular reprogramming

On September 1, Matteo Ciarcià and Steffen Rulands published a theoretical preprint on bioRxiv. In a minimal model and computer simulations, transient expression of OSK(M), proteins that alter gene regulation, produces three distinct outcomes. In the model, epigenetic marks that regulate gene activity reorganize faster than the three-dimensional folding of DNA.

Partial reprogramming is intended to reverse age-related patterns of gene activity while preserving cell identity. In their model, the authors linked epigenetic marks to chromatin, which consists of DNA and proteins in the nucleus. The marks influence chromatin packaging, while contacts between distant regions of DNA maintain similar distributions of these marks.

After a short pulse, the model returns almost to its initial state. With an intermediate pulse duration, the average balance of marks becomes sensitive to small perturbations near the boundary between stable states. The chromatin remains compact and retains its network of long-range contacts. After OSK(M) is switched off, this network restores correlations between the marks. A long pulse makes the chromatin more open, reduces the number of long-range contacts, and erases the memory encoded in these correlations.

The authors tested one prediction of the model using published data from mouse cells. In embryonic fibroblasts, correlations in the repressive epigenetic mark H3K9me3 decayed more slowly in the denser B compartments of chromatin than in the open A compartments. The difference was smaller in embryonic stem cells, where chromatin compartmentalization was less pronounced. This observation is qualitatively consistent with the model's proposed relationship between chromatin compaction and the range of epigenetic correlations.

In a 2025 preprint, Ciarcià, Benjamin Simons, and Rulands described three timescales of methylation change: rapid molecular events, intermediate dynamics, and slow transitions. The new study extends this framework by incorporating the three-dimensional organization of chromatin. The authors propose measuring chromatin contacts and several epigenetic marks over time during OSK(M) induction. According to the model, changes in chromatin compaction or in the feedback between the reading and deposition of marks should shift the boundaries between the three regimes.