Bottom–up modeling of chromatin segregation due to epigenetic modifications

MacPherson, Quinn; Beltran, Bruno; Spakowitz, Andrew J.

doi:10.1073/pnas.1812268115

Cited by 148 publications

(178 citation statements)

References 47 publications

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“…Importantly, treating chromatin fibres as BCPs has been used with considerable success to accurately simulate contact maps derived from Hi-C experiments (154,(163)(164)(165)(166).…”

Section: Heterochromatin-like Domains/complexes and Compartmentalisationmentioning

confidence: 99%

“…"bridging" of H3K9me2/3-marked nucleosomes within the complexes is reconstituted resulting in de-mixing and micro-phase separation ( Figure 7F) as observed for "blocks" in a BCP. Even the smallest heterochromatin-like complexes are likely to phase separate; polymer simulations and chromatin fragmentation experiments indicate that the minimal size of a chromatin "block" required for phase separation is around ~10-20kb (163,174). The newly micro-phase separated complexes ("blocks") can then engage in cis-and trans-contacts mediated by HP1…”

Section: Heterochromatin-like Domains/complexes and Hi-c Mapsmentioning

confidence: 99%

“…between H3K9me3-marked nucleosomes 46,74,77 and, (iii), HP1 can also act as a bridge between distantly located loci 73,74 , it is unsurprising that the KRAB-ZNF heterochromatin-like domains ("blocks") make far cis-contacts that emerge as the B4 sub compartment in Hi-C maps 105 . Importantly, treating chromatin fibres as BCPs has been used with considerable success to accurately simulate contact maps derived from Hi-C experiments 154,[163][164][165][166] .…”

Section: Heterochromatin-like Domains/complexes and Compartmentalisationmentioning

confidence: 99%

“…Even the smallest heterochromatin-like complexes are likely to phase separate; polymer simulations and chromatin fragmentation experiments indicate that the minimal size of a chromatin "block" required for phase separation is around ~10-20kb 163,174 . The newly micro-phase separated complexes ("blocks") can then engage in cis-and trans-contacts mediated by HP1 "bridging" of H3K9me2/3-marked nucleosomes ( Figure 7F and red arrows in bottom row of Figure 7).…”

Section: Heterochromatin-like Domains/complexes and Hi-c Mapsmentioning

confidence: 99%

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On the relation of phase separation and Hi-C maps to epigenetics

Singh

Newman²

2019

Preprint

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The relationship between compartmentalisation of the genome and epigenetics is long and hoary. In 1928 Heitz defined heterochromatin as the largest differentiated chromatin compartment in eukaryotic nuclei. Müller's (1930) discovery of position-effect variegation (PEV) went on to show that heterochromatin is a cytologically-visible state of heritable (epigenetic) gene repression. Current insights into compartmentalisation have come from a high-throughput top-down approach where contact frequency (Hi-C) maps revealed the presence of compartmental domains that segregate the genome into heterochromatin and euchromatin. It has been argued that the compartmentalisation seen in Hi-C maps is due to the physiochemical process of phase separation. Oddly, the insights provided by these experimental and conceptual advances have remained largely silent on how Hi-C maps and phase separation relate to epigenetics. Addressing this issue directly in mammals we have made use of a bottom-up approach starting with the hallmarks of constitutive heterochromatin, heterochromatin protein 1 (HP1) and its binding partner the H3K9me2/3 determinant of the histone code. They are key epigenetic regulators in eukaryotes. Both hallmarks are also found outside mammalian constitutive heterochromatin as constituents of larger (0.1-5Mb) heterochromatin-like domains and smaller (less than 100Kb) complexes. The well-documented ability of HP1 proteins to function as bridges between H3K9me2/3-marked nucleosomes enables cross-linking within and between chromatin fibres that contributes to polymer-polymer phase separation (PPPS) that packages epigenetically-heritable chromatin states during interphase. Contacts mediated by HP1 "bridging" are likely to have been detected in Hi-C maps, as evidenced by the B4 heterochromatic sub-compartment that emerges from contacts between large KRAB-ZNF heterochromatin-like domains. Further, mutational analyses have revealed a finer, innate, compartmentalisation in Hi-C experiments that likely reflect contacts involving smaller domains/complexes. Proteins that bridge (modified) DNA and histones in nucleosomal fibres -where the HP1-H3K9me2/3 interaction represents the most evolutionarilyconserved paradigm -could drive and generate the fundamental compartmentalisation of the interphase nucleus.This has implications for the mechanism(s) that maintains cellular identity, be it a terminally-differentiated fibroblast or a pluripotent embryonic stem cell.

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“…Importantly, treating chromatin fibres as BCPs has been used with considerable success to accurately simulate contact maps derived from Hi-C experiments (154,(163)(164)(165)(166).…”

Section: Heterochromatin-like Domains/complexes and Compartmentalisationmentioning

confidence: 99%

Section: Heterochromatin-like Domains/complexes and Hi-c Mapsmentioning

confidence: 99%

Section: Heterochromatin-like Domains/complexes and Compartmentalisationmentioning

confidence: 99%

Section: Heterochromatin-like Domains/complexes and Hi-c Mapsmentioning

confidence: 99%

See 2 more Smart Citations

On the relation of phase separation and Hi-C maps to epigenetics

Singh

Newman²

2019

Preprint

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“…where l and l′ represent the number of methylated and demethylated nucleosomes in the assembly, respectively. Unlike other polymer models (MacPherson et al, 2018;Nuebler et al, 2018) , we do not explicitly model physical connections between nucleosomes due to DNA; such connections would be expected to result in a spatial dependence of reaction rates within this chromatin domain; however, as the entire domain (100 nucleosomes) has a length scale greater than the persistence length of chromatin (~15-20 nucleosomes, from (Arbona et al, 2017), and would thus enable free interactions between non-neighboring nucleosomes, we would expect the essential properties of our minimal model would also hold in a more realistic physical model that incorporates nucleosome connectedness.…”

mentioning

confidence: 99%

Temporal scaling in developmental gene networks by epigenetic timing control

Nguyen

Pease

Irwin

et al. 2019

Preprint

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During development, progenitors follow defined temporal schedules for differentiation, to form organs and body plans with precise sizes and proportions. Across diverse contexts, these developmental schedules are encoded by autonomous timekeeping mechanisms in single cells.These autonomous timers not only operate robustly over many cell generations, but can also operate at different speeds in different species, enabling proportional scaling of temporal schedules and population sizes. By combining mathematical modeling with live-cell measurements, we elucidate the mechanism of a polycomb-based epigenetic timer, that delays activation of the T-cell commitment regulator Bcl11b to facilitate progenitor expansion. This mechanism generates activation delays that are independent of cell cycle duration, and are tunably controlled by transcription factors and epigenetic modifiers. When incorporated into regulatory gene networks, this epigenetic timer enables progenitors to set scalable temporal schedules for flexible size control. These findings illuminate how evolution may set and adjust developmental speed in multicellular organisms.

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Bridging chromatin structure and function over a range of experimental spatial and temporal scales by molecular modeling

Portillo‐Ledesma

Schlick

2019

WIREs Comput Mol Sci

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Chromatin structure, dynamics, and function are being intensely investigated by a variety of methods, including microscopy, X‐ray diffraction, nuclear magnetic resonance, biochemical crosslinking, chromosome conformation capture, and computation. The modeling helps interpret experimental data and generate configurations and mechanisms related to the three‐dimensional organization and function of the genome. Experimental contact maps, in particular, as obtained by a variety of chromosome conformation capture methods, are of increasing interest due to their implications on genome structure and regulation on many levels. In this perspective, using seven examples from our group's studies, we illustrate how molecular modeling can help interpret such experimental data. Specifically, we show how computed contact maps related to experimental systems can help interpret structures of nucleosomes, chromatin higher‐order folding, domain segregation mechanisms, gene organization, and the effect on chromatin structure of external and internal fiber parameters, such as nucleosome positioning, presence of nucleosome free regions, histone post‐translational modifications, and linker histone binding. We argue that such computations on multiple spatial and temporal scales will be increasingly important for the integration of genomic, epigenomic, and biophysical data on chromatin structure and related cellular processes. This article is categorized under: Structure and Mechanism > Computational Biochemistry and Biophysics

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Bottom–up modeling of chromatin segregation due to epigenetic modifications

Cited by 148 publications

References 47 publications

On the relation of phase separation and Hi-C maps to epigenetics

On the relation of phase separation and Hi-C maps to epigenetics

Temporal scaling in developmental gene networks by epigenetic timing control

Bridging chromatin structure and function over a range of experimental spatial and temporal scales by molecular modeling

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