Shaping epigenetic memory via genomic bookmarking

Michieletto, Davide; Chiang, Michael; Colì, Davide; Papantonis, Argyris; Orlandini, Enzo; Cook, Peter R.; Marenduzzo, Davide

doi:10.1093/nar/gkx1200

Cited by 69 publications

(106 citation statements)

References 87 publications

(158 reference statements)

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“…30, 2018; Our magnetic polymer model for epigenomic ordering can be extended in a number of ways. One is by introducing genomic bookmarking to seed domain formation [16]. Another interesting avenue to explore would be to pursue a spin-glass model [51] instead of a Potts model for the underlying polymeric ordering.…”

Section: Discussionmentioning

confidence: 99%

“…These models describe each chromosome as a magnetic polymer whose monomers encode (epigenetic) states which can change over time; they are therefore in the same universality class of annealed copolymers without global conservation laws [23]. This model is markedly different from previous works on annealed copolymers with conserved number of elements in each state [24][25][26], and can be seen as a generalisation of the 1D Ising (or Potts) system where the substrate is allowed to diffuse in 3D space [15,16,27]. We combine analytical mean-field theories with Brownian Dynamics (BD) simulations to simultaneously map the distribution of epigenetic marks and the 3D genomic arrangement within the cell nucleus.…”

mentioning

confidence: 99%

“…The interplay between spatial genome organisation and epigenetic patterns guides the tissue-specific selection of which genes will be translated into proteins, in turn determining cellular identity [3,5,[12][13][14]. One of the outstanding problems in biophysics is to understand how genome organisation and epigenetic patterns are linked to each other dynamically and what are the physical principles through which they regulate genome functionality and cellular memory [15][16][17][18][19][20][21].…”

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confidence: 99%

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Magnetic Polymer Models for Epigenomic Organisation and Phase Separation

Colì

Michieletto

Marenduzzo

et al. 2018

Preprint

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The genetic instructions stored in the genome require an additional layer of information to robustly determine cell fate. This additional regulation is provided by the interplay between chromosome-patterning biochemical ("epigenetic") marks and threedimensional genome folding. Yet, the physical principles underlying the dynamical coupling between three-dimensional genomic organisation and one-dimensional epigenetic patterns remain elusive. To shed light on this issue, here we study by mean field theory and Brownian dynamics simulations a magnetic polymer model for chromosomes, where each monomer carries a dynamic epigenetic mark. At the single chromosome level, we show that a first order transition describes the unlimited spreading of epigenetic marks, a phenomenon that is often observed in vivo. At the level of the whole nucleus, experiments suggest chromosomes form micro-phase separated compartments with distinct epigenetic marks. We here discover that for a melt of magnetic polymers such a morphology is thermodynamically unstable, but can be stabilised by a nonequilibrium and ATP-mediated epigenetic switch between different monomer states.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Magnetic Polymer Models for Epigenomic Organisation and Phase Separation

Colì

Michieletto

Marenduzzo

et al. 2018

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“…[86,89,90]). Further, by considering a longer region of a human chromosome folded as predicted by the above mentioned polymer models [48,49,56], we discovered that at larger scales HIV integration sites obtained from experiments [79] are predominantly determined by chromatin accessibility. Thus, by accounting for DNA elasticity and chromatin accessibility -two universal and cell unspecific features of genome organisation -our model could predict HIV integration patterns remarkably similar to those observed in experiments in vitro [81,82] and in vivo [79].…”

Section: A Polymer Model For Hiv Integrationmentioning

confidence: 99%

Integrating Transposable Elements in the 3D Genome

Bousios

Nuetzmann

Buck

et al. 2019

Preprint

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Chromosome organisation is increasingly recognised as an essential component of genome regulation, cell fate and cell health. Within the realm of transposable elements (TEs) however, the spatial information of how genomes are folded is still only rarely integrated in experimental studies or accounted for in modelling. Here, we propose a new predictive modelling framework for the study of the integration patterns of TEs based on extensions of widely employed polymer models for genome organisation. Whilst polymer physics is recognised as an important tool to understand the mechanisms of genome folding, we now show that it can also offer orthogonal and generic insights into the integration and distribution profiles (or "topography") of TEs across organisms. Here, we present polymer physics arguments and molecular dynamics simulations on TEs inserting into heterogeneously flexible polymers and show with a simple model that polymer folding and local flexibility affects TE integration patterns. The preliminary discussion presented herein lay the foundations for a large-scale analysis of TE integration dynamics and topography as a function of the three-dimensional host genome. BACKGROUND

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“…The heterochromatin-like complex so targeted nucleates the subsequent "spreading" and formation of a larger domain ( Figure 4B). A coarse-grained polymer model of genomic bookmarking predicts, as one of three parameters required for robust epigenetic inheritance of chromatin states, a critical density of bookmarks along a chromatin fibre to be 1 or 10 nucleosomes per 400 nucleosomes (φ c ~0.04; (154) HP1β around the KAP1sites gives the size of the nucleation site at ~6kB ( Figure 5D), which is in agreement with previous studies (104,114). This indicates an approximate density of bookmarks of ~30 nucleosomes per 200 nucleosomes in the B4 sub-compartment, well within the critical density defined by the coarse-grained polymer model.…”

Section: Genomic Bookmarking and Epigenetic Inheritancementioning

confidence: 99%

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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Shaping epigenetic memory via genomic bookmarking

Cited by 69 publications

References 87 publications

Magnetic Polymer Models for Epigenomic Organisation and Phase Separation

Magnetic Polymer Models for Epigenomic Organisation and Phase Separation

Integrating Transposable Elements in the 3D Genome

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

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