Single-cell chromatin state transitions during epigenetic memory formation
11 affiliations
- 1Department of Bioengineering, Stanford University, Stanford, CA, USA
- 2Biophysics Program, Stanford University, Stanford, CA, USA
- 3Department of Genetics, Stanford University, Stanford, CA, USA
- 4Department of Chemical & Systems Biology, Stanford University, Stanford, CA, USA
- 5Department of Dermatology, Program in Epithelial Biology, Stanford University, Stanford, CA, USA
- 6Program in Cancer Biology, Stanford University, Stanford, CA, USA
- 7Department of Developmental Biology, Stanford University, Stanford, CA, USA
- 8Department of Discovery Oncology, Genentech, CA, USA
- 9Chan Zuckerberg Biohub, San Francisco, CA, USA
- 10Department of Applied Physics, Stanford University, Stanford, CA, USA
- 11Stanford University
Abstract
Repressive chromatin modifications compact chromatin and mediate heritable gene silencing, but how structural changes quantitatively relate to epigenetic memory remains unclear. Using targeted recruitment of the KRAB repressor to induce H3K9me3 at a reporter gene, combined with single-molecule 3D chromatin imaging, we show that irreversible silencing is associated with large-scale chromatin compaction across tens of kilobases. In contrast, histone deacetylation produces reversible silencing without such compaction. Despite substantial single-cell heterogeneity, average compaction at the end of silencing quantitatively predicts epigenetic memory weeks after KRAB removal. Here, memory arises not through stable H3K9me3 domains but rather through a dynamic handoff in which H3K9me3 is gradually lost and replaced by DNA methylation. Stochastic simulations recapitulating these dynamics suggest that compaction enhances read-write feedback to promote this transition. Similar compaction is observed at endogenous loci during differentiation and fate commitment, suggesting that spatial organization may be predictive of epigenetic memory in other systems.
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BibTeX
@article{fujimori2026singlecell,
title = {{Single-cell chromatin state transitions during epigenetic memory formation}},
author = {Taihei Fujimori and Abby R. Thurm and Simon Gaudin and Owen R. S. Dunkley and Carolina Rios-Martinez and Michaela M. Hinks and Benjamin R. Doughty and Joydeb Sinha and Derek J. Le and Antonina Hafner and William James Greenleaf and Alistair Nicol Boettiger and Lacramioara Bintu},
journal = {Science Advances},
year = {2026},
month = jul,
doi = {10.1126/sciadv.aeb0060},
url = {https://doi.org/10.1126/sciadv.aeb0060},
note = {CC BY},
}
RIS
TY - JOUR
TI - Single-cell chromatin state transitions during epigenetic memory formation
AU - Taihei Fujimori
AU - Abby R. Thurm
AU - Simon Gaudin
AU - Owen R. S. Dunkley
AU - Carolina Rios-Martinez
AU - Michaela M. Hinks
AU - Benjamin R. Doughty
AU - Joydeb Sinha
AU - Derek J. Le
AU - Antonina Hafner
AU - William James Greenleaf
AU - Alistair Nicol Boettiger
AU - Lacramioara Bintu
PY - 2026
DA - 2026/07/23
JO - Science Advances
DO - 10.1126/sciadv.aeb0060
UR - https://doi.org/10.1126/sciadv.aeb0060
AB - Repressive chromatin modifications compact chromatin and mediate heritable gene silencing, but how structural changes quantitatively relate to epigenetic memory remains unclear. Using targeted recruitment of the KRAB repressor to induce H3K9me3 at a reporter gene, combined with single-molecule 3D chromatin imaging, we show that irreversible silencing is associated with large-scale chromatin compaction across tens of kilobases. In contrast, histone deacetylation produces reversible silencing without such compaction. Despite substantial single-cell heterogeneity, average compaction at the end of silencing quantitatively predicts epigenetic memory weeks after KRAB removal. Here, memory arises not through stable H3K9me3 domains but rather through a dynamic handoff in which H3K9me3 is gradually lost and replaced by DNA methylation. Stochastic simulations recapitulating these dynamics suggest that compaction enhances read-write feedback to promote this transition. Similar compaction is observed at endogenous loci during differentiation and fate commitment, suggesting that spatial organization may be predictive of epigenetic memory in other systems.
SN - 2375-2548
ER -