Analog epigenetic memory revealed by targeted chromatin editing
Open accessPreprint — published as 10.1016/j.xgen.2025.100985
Abstract
Summary: Chemical modifications to histones and DNA play a crucial role in the regulation of transcription and in the maintenance of chromatin states that are not permissive to gene expression [1–3]. However, the landscape of gene expression states that these modifications stably maintain remains uncharted. Here, we show that gene expression can be memorized at a wide range of levels thus implementing analog epigenetic memory. Mechanistically, we find that DNA methylation serves a primary role in maintaining memory across cell divisions while histone modifications only follow DNA methylation to regulate gene expression. Employing targeted epigenetic editing and time-course analysis, we analyzed the temporal stability of gene expression and DNA methylation post removal of epigenetic effectors. We found that the grade of DNA methylation in the gene’s promoter, defined as the mean fraction of methylated CpGs, remains stable over time and inversely correlates with gene expression level. By contrast, Histone 3 lysine 9 trimethylation (H3K9me3) could not persist after removal of its writer in the absence of DNA methylation. These experimental findings, combined with our chromatin modification model, indicate that the absence of positive feedback mechanisms around DNA methylation - unlike those found in histone modifications - enable the temporal stability of the DNA methylation grade, which leads to analog memory. These results expand current knowledge on how epigenetic memory is achieved in natural systems. Moreover, we anticipate that analog memory through graded DNA methylation will enable to program mammalian cells with fine-grained information storage. This capability will significantly enhance the sophistication of engineered cell functionality in applications including tissue engineering, organoids, and cell therapies.
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Salibi, E., Palacios, S., lu, E. E. A., Weiss, R., Schlaeger, T. M., Collins, J. J., & Vecchio, D. D. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.10.28.685244 · Cited by 1 · see citing works
Self-citationA Physics-based Model Reveals Mechanisms of Epigenetic MemoryPreprint
Navarro, E. J., Poole, W., Lismer, A., Qu, J., Kafetzopoulos, I., Parry, A., Ijaz, J., Santambrogio, A., Spangler, R., Martín-Zamora, F. M., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.01.16.699330
Stochastic modeling of epigenetic memory
Bruno, S., & Vecchio, D. D. (2026) · npj Systems Biology and Applications · doi:10.1038/s41540-026-00664-9
Self-citationGraded versus ON/OFF control in quantitative gene expression and epigenetic memory
Dean, C., & Howard, M. (2026) · The EMBO Journal · doi:10.1038/s44318-026-00750-y
Targeting DNA Methylation: New Paradigms and the Advent of Gene-Selective Tools
Gilbert, J., & Calzaferri, F. (2026) · Chemical Research in Toxicology · doi:10.1021/acs.chemrestox.6c00218
Written in development and lost in ageing: the grammar of cellular identity
Yücel, A. D., Molière, A., & Gladyshev, V. N. (2026) · Nature · doi:10.1038/s41586-026-10955-0
- Authors
- Palacios, S., Bruno, S., Weiss, R., Salibi, E., Kane, A., Ilia, K., & Del Vecchio, D.
- Affiliations
- Massachusetts Institute of Technology (US)
- Dana-Farber Cancer Institute (US)
- Venue
- Cell Genomics
- Publisher
- openRxiv
- Published
- 2024-02-16
- Volume
- 5
- Issue
- 11
- Pages
- 100985-100985
- ISSN
- 2666-979X (ISSN-L)
- OpenAlex
- W4414111079
- Cited by
- 13
- References
- 88
- Citations by year
- 2026: 8 · 2025: 5
- FWCI
- 3.91
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc-nd
- www.biorxiv.org/about/FAQ#license (vor)
- Locations
- Cell Genomics (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Science Foundation (2027949)
- U.S. Department of Defense
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
- Keywords
- chromatin modification, DNA methylation, histone modifications, positive feedback, synthetic biology
- MeSH terms
- Gene Editing, Epigenetic Memory, Chromatin, Histones, Humans, DNA Methylation, Histone Code, Epigenesis, Genetic
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