Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 113, Issue 29, Pages E4180-E4189Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1605862113
Keywords
epigenetic memory; heterochromatin; epigenome editing; histone modification; stochastic simulation
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Funding
- German Federal Ministry of Education and Research (BMBF) Grant of the Services@MediGRID program [01IG07015G]
- European Molecular Biology Organization (EMBO) [LTF 187-2014]
- NIH [R01GM082848, R01GM074739]
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Histone modifications can redistribute along the genome in a sequence-independent manner, giving rise to chromatin position effects and epigenetic memory. The underlying mechanisms shape the endogenous chromatin landscape and determine its response to ectopically targeted histone modifiers. Here, we simulate linear and looping-driven spreading of histone modifications and compare both models to recent experiments on histone methylation in fission yeast. We find that a generalized nucleation-and-looping mechanism describes key observations on engineered and endogenous methylation domains including intrinsic spatial confinement, independent regulation of domain size and memory, variegation in the absence of antagonists, and coexistence of short-and long-term memory at loci with weak and strong constitutive nucleation. These findings support a straightforward relationship between the biochemical properties of chromatin modifiers and the spatiotemporal modification pattern. The proposed mechanism gives rise to a phase diagram for cellular memory that may be generally applicable to explain epigenetic phenomena across different species.
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