Impact of chromosomal organization on epigenetic drift and domain stability revealed by physics-based simulations

Wakim, Joseph G.; Sandholtz, Sarah H.; Spakowitz, Andrew J.

doi:10.1016/j.bpj.2021.10.019

Cited by 10 publications

(14 citation statements)

References 85 publications

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“…4K ). This behavior is reminiscent of previous chromatin models based on homotypic polymer interactions ( 15, 37, 48, 49, 55, 60–64 ). Within the globule, 3D interactions between neighboring blue beads were transient, and beads rapidly exchanged 3D neighbors while maintaining a spheroidal organization – much like molecules in a liquid droplet (even though the beads are still chained together in a polymer, not a true liquid).…”

Section: Resultssupporting

confidence: 65%

“…By incorporating the multi-state nature of Pc-chromatin into our simulations we find a regime in which the structures may make frequent excursions into decompact and intermixed states, (as also seen in the distribution of structures in our ORCA data) and still provide a major boost to the domain stability compared to a system lacking spatial feedback. The simulations also identified a liability of the droplet-forming regime examined in prior models (44,48,49), which is at greater risk of stabilizing ectopic domains. In our model, spatial and biochemical feedback combine to ensure robust epigenetic inheritance.…”

Section: Discussionmentioning

confidence: 83%

“…The 3D polymer dynamics in these simulations were computed using the polychrom framework from open2c ( 45 ), derived from earlier models of chromatin folding by the Mirny lab ( 46, 47 ). The recoloring dynamics (modeling PcG biochemical interactions) were added onto this as described in the methods and our deposited code (see Supplement ), similar to the approach used in recent work ( 44, 48, 49 ).…”

Section: Resultsmentioning

confidence: 99%

“…The theoretical effects of interactions between changing chemical identities and flexible 3D structure of a polymer has been less explored. The few pioneering works in this area have yet to be applied to data or Polycomb biology ( 44, 48, 49, 60 ). Notably, we found these simulations that combined spatial and chemical interactions were able to produce behaviors that capture key features of our microscopy data.…”

Section: Resultsmentioning

confidence: 99%

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Polycomb repression of Hox genes involves spatial feedback but not domain compaction or demixing

Murphy

Boettiger

2022

Preprint

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Polycomb group (PcG) proteins modulate higher-order genome folding and play a critical role in silencing transcription during development. It is commonly proposed that PcG dependent changes in genome folding, which compact chromatin, contribute directly to repression by blocking binding of activating complexes and demixing repressed targets from non-repressed chromatin. To test this model we utilized Optical Reconstruction of Chromatin Architecture (ORCA) to trace the 3-dimensional folding of the Hoxa gene cluster, a canonical Polycomb target, allowing us to analyze thousands of DNA traces in single cells. In cell types ranging from embryonic stem cells to brain tissue, we find that PcG-bound chromatin frequently explores decompact states and partial mixing with neighboring chromatin, while remaining uniformly repressed, challenging the repression-by-compaction model. Using polymer physics simulations, we show that the flexible ensembles we observe can be explained by dynamic contacts mediated by multivalent interactions that are too weak to induce phase separation. Instead, these transient contacts contribute to accurate propagation of the epigenetic state without ectopic spreading or gradual erosion. We propose that the distinctive 3D organization of Polycomb chromatin, reflects a mechanism of 'spatial feedback' required for stable repression.

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Section: Resultssupporting

confidence: 65%

Section: Discussionmentioning

confidence: 83%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Polycomb repression of Hox genes involves spatial feedback but not domain compaction or demixing

Murphy

Boettiger

2022

Preprint

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“…4C). In particular, we found that these profiles are very sensitive to the underlying spreading capacity of HMEs [101], longer-range mechanisms facilitating the percolation of the system into large contact domains at low state-dependent recruitment (Fig. 5C) [27].…”

Section: Discussionmentioning

confidence: 99%

Painters in chromatin: a unified quantitative framework to systematically characterize epigenome regulation and memory

Abdulla

Vaillant

Jost

2022

Preprint

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In eukaryotes, many stable and heritable phenotypes arise from the same DNA sequence, owing to epigenetic regulatory mechanisms relying on the molecular cooperativity of "reader-writer'' enzymes. In this work, we focus on the fundamental, generic mechanisms behind the epigenome memory encoded by post-translational modifications of histone tails. Based on experimental knowledge, we introduce a unified modeling framework, the painter model, describing the mechanistic interplay between sequence-specific recruitment of chromatin regulators, chromatin-state-specific reader-writer processes and long-range spreading mechanisms. A systematic analysis of the model building blocks highlights the crucial impact of tridimensional chromatin organization and state-specific recruitment of enzymes on the stability of epigenomic domains and on gene expression. In particular, we show that enhanced 3D compaction of the genome and enzyme limitation facilitate the formation of ultra-stable, confined chromatin domains. The model also captures how chromatin state dynamics impact the intrinsic transcriptional properties of the region, slower kinetics leading to noisier expression. We finally apply our framework to analyze experimental data, from the propagation of γH2AX around DNA breaks in human cells to the maintenance of heterochromatin in fission yeast, illustrating how the painter model can be used to extract quantitative information on epigenomic molecular processes.

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Computer simulations of chromatin phase separation

Schiessel

2022

Biophysical Journal

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Impact of chromosomal organization on epigenetic drift and domain stability revealed by physics-based simulations

Cited by 10 publications

References 85 publications

Polycomb repression of Hox genes involves spatial feedback but not domain compaction or demixing

Polycomb repression of Hox genes involves spatial feedback but not domain compaction or demixing

Painters in chromatin: a unified quantitative framework to systematically characterize epigenome regulation and memory

Computer simulations of chromatin phase separation

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