Epigenetics meets mathematics: Towards a quantitative understanding of chromatin biology

Steffen, Philipp A.; Fonseca, João Pedro; Ringrose, Leonie

doi:10.1002/bies.201200076

Cited by 30 publications

(27 citation statements)

References 97 publications

(161 reference statements)

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“…24 Its loss leads to a release of heterochromatin from the periphery in the nuclei of C. elegans embryos, perfectly fulfilling the initial experimental hypothesis. Furthermore, analysis of CEC-4 localization revealed that it is concentrated at the nuclear rim.…”

Section: Pathways Of Heterochromatin Sequestration At the Nuclear Persupporting

confidence: 71%

Spatial segregation of heterochromatin: Uncovering functionality in a multicellular organism

Cabianca

Gasser

2016

Nucleus

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Section: Pathways Of Heterochromatin Sequestration At the Nuclear Persupporting

confidence: 71%

Spatial segregation of heterochromatin: Uncovering functionality in a multicellular organism

Cabianca

Gasser

2016

Nucleus

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“…The extracted diffusion coefficients given by FCS and FRAP were in reasonably good agreement with each other, with the exception of EGFP:ASH1, for which a slower diffusion coefficient was extracted from FRAP than from FCS data (Supplementary Figure S7A). This may comprise both the true diffusion and a binding component, or may also be due to chromatin movements during the longer measurement times used in ASH1 FRAP experiments (18,30). In all cases, diffusion was slower than expected for the monomeric protein, suggesting that these proteins participate in high-molecular weight complexes (Supplementary Figure S7B).…”

Section: Resultsmentioning

confidence: 99%

“…These studies demonstrate that PRC1 complexes bind chromatin by simple chemical equilibria (15). Given this observation, it has been proposed that developmental transitions in PcG and TrxG regulation may be a matter of quantitative, rather than qualitative change (18). To understand dynamic aspects of regulation by PcG and TrxG proteins, it is crucial to gain quantitative information about their absolute molecule numbers, molar concentrations and kinetic chromatin-binding properties in living animals.…”

Section: Introductionmentioning

confidence: 99%

Quantitative in vivo analysis of chromatin binding of Polycomb and Trithorax group proteins reveals retention of ASH1 on mitotic chromatin

Steffen

Fonseca

Gänger

et al. 2013

Nucleic Acids Research

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The Polycomb (PcG) and Trithorax (TrxG) group proteins work antagonistically on several hundred developmentally important target genes, giving stable mitotic memory, but also allowing flexibility of gene expression states. How this is achieved in quantitative terms is poorly understood. Here, we present a quantitative kinetic analysis in living Drosophila of the PcG proteins Enhancer of Zeste, (E(Z)), Pleiohomeotic (PHO) and Polycomb (PC) and the TrxG protein absent, small or homeotic discs 1 (ASH1). Fluorescence recovery after photobleaching and fluorescence correlation spectroscopy reveal highly dynamic chromatin binding behaviour for all proteins, with exchange occurring within seconds. We show that although the PcG proteins substantially dissociate from mitotic chromatin, ASH1 remains robustly associated with chromatin throughout mitosis. Finally, we show that chromatin binding by ASH1 and PC switches from an antagonistic relationship in interphase, to a cooperative one during mitosis. These results provide quantitative insights into PcG and TrxG chromatin-binding dynamics and have implications for our understanding of the molecular nature of epigenetic memory.

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“…Measurements show that the typical residence time of a modification enzyme on chromatin is within sub-seconds to a few minutes [4]. Experimental observations also suggest that a modified nucleosome may have higher binding affinity for the corresponding enzymes [3,[9][10][11].…”

mentioning

confidence: 96%

Statistical Mechanics Model for the Dynamics of Collective Epigenetic Histone Modification

et al. 2014

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Epigenetic histone modifications play an important role in the maintenance of different cell phenotypes. The exact molecular mechanism for inheritance of the modification patterns over cell generations remains elusive. We construct a Potts-type model based on experimentally observed nearest-neighbor enzyme lateral interactions and nucleosome covalent modification state biased enzyme recruitment. The model can lead to effective nonlocal interactions among nucleosomes suggested in previous theoretical studies, and epigenetic memory is robustly inheritable against stochastic cellular processes.PACS numbers: 82.39. Rt, 87.17.Aa, 87.16.Yc, 87.16.A Nucleosomes are basic organizational units of chromatin in eukaryotic cells. A typical nucleosome has approximately 147 base pairs wrapped around a histone octamer and are interconnected by linker DNA of varying length (see Fig. 1) [1,2]. Covalent modifications of several amino acid residues on the histone core can lead to either active or repressive gene expression activities [3]. A dynamic equilibrium in the nucleosome modification state is attained due to a 'tug-of-war' between the associated covalent mark addition and removal enzymes [4]. The system may show a bistable behavior due to coexistence of repressive and active epigenetic states for different copies of a gene within the same cell [5].Experiments suggest that at least some of the nucleosome covalent patterns can be transmitted over a number of generations [1]. Although the actual mechanism for this epigenetic memory is unclear, a simple rule-based model by Dodd et al. [5] shows that robust bistability requires cooperative effects beyond neighboring nucleosomes, which they suggest is due to compact chromatin structures. Subsequent theoretical studies on yeast chromatin silencing [6], mouse stem cell differentiation [7], and plant flowering regulation [8] also conclude that this nonlocal cooperativity is necessary for generating stable epigenetic memory.In recent years molecular details on nucleosome covalent modification dynamics have been extensively studied. Measurements show that the typical residence time of a modification enzyme on chromatin is within sub-seconds to a few minutes [4]. Experimental observations also suggest that a modified nucleosome may have higher binding affinity for the corresponding enzymes [3,[9][10][11]. Another interesting observation is that a nucleosome bound modification enzyme complex laterally interacts with another bound to neighboring nucleosomes [10,12,13].Although the functional consequences of these interactions on epigenetic dynamics are unclear, recent work suggests that increased [14,15].In this work we construct a theoretical model aiming to bridge the gap between detailed molecular events occurring at the sub-second time scale, and the long-time scale epigenetic change dynamics that is typically in days or longer. To be specific we focus on lysine 4 (active) and lysine 9 (repressive) methylation on histone H3, although we expect the mechanism discussed here can be...

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Epigenetics meets mathematics: Towards a quantitative understanding of chromatin biology

Cited by 30 publications

References 97 publications

Spatial segregation of heterochromatin: Uncovering functionality in a multicellular organism

Spatial segregation of heterochromatin: Uncovering functionality in a multicellular organism

Quantitative in vivo analysis of chromatin binding of Polycomb and Trithorax group proteins reveals retention of ASH1 on mitotic chromatin

Statistical Mechanics Model for the Dynamics of Collective Epigenetic Histone Modification

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