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Modeling the dynamics of bivalent histone modifications.

Ku WL, Girvan M, Yuan GC, Sorrentino F, Ott E - PLoS ONE (2013)

Bottom Line: It is generally agreed that bivalent domains play an important role in stem cell differentiation, but the underlying mechanisms remain unclear.Here we formulate a mathematical model to investigate the dynamic properties of histone modification patterns.We then illustrate that our modeling framework can be used to capture key features of experimentally observed combinatorial chromatin states.

View Article: PubMed Central - PubMed

Affiliation: Department of Physics, University of Maryland, College Park, Maryland, United States of America ; Institute for Research in Electronics and Applied Physics, University of Maryland, College Park, Maryland, United States of America.

ABSTRACT
Epigenetic modifications to histones may promote either activation or repression of the transcription of nearby genes. Recent experimental studies show that the promoters of many lineage-control genes in stem cells have "bivalent domains" in which the nucleosomes contain both active (H3K4me3) and repressive (H3K27me3) marks. It is generally agreed that bivalent domains play an important role in stem cell differentiation, but the underlying mechanisms remain unclear. Here we formulate a mathematical model to investigate the dynamic properties of histone modification patterns. We then illustrate that our modeling framework can be used to capture key features of experimentally observed combinatorial chromatin states.

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6-state model.Illustration of the states in the 6-state model. Circles represent nucleosomes. A nucleosome contains two histones copies represented by the vertically oriented ellipses. Each histone has two sites, one site (represented by the upper half of the ellipse) that can be either unmodified (symbolized by ) or have an active mark (symbolized by ), and another site (represented by the lower half of the ellipse) that can be either unmodified (symbolized by ) or have a repressive mark (symbolized by ). (Note that the physical nucleosome states labeled ,  and  could be just as well depicted by interchanging the left and right ellipses within the respective circles.).
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pone-0077944-g001: 6-state model.Illustration of the states in the 6-state model. Circles represent nucleosomes. A nucleosome contains two histones copies represented by the vertically oriented ellipses. Each histone has two sites, one site (represented by the upper half of the ellipse) that can be either unmodified (symbolized by ) or have an active mark (symbolized by ), and another site (represented by the lower half of the ellipse) that can be either unmodified (symbolized by ) or have a repressive mark (symbolized by ). (Note that the physical nucleosome states labeled , and could be just as well depicted by interchanging the left and right ellipses within the respective circles.).

Mentions: We consider a 1D lattice of nucleosomes, where there is a nucleosome at each lattice site . An actual nucleosome consists of 8 histone protein molecules, that can be regarded as two identical groups of four each. In what follows we only consider the state of one of these four histone group members, namely the H3 histone, which is specifically related to bivalency. Thus, in our model, we represent the state of a nucleosome as being determined by the states of its two H3 histone copies. There are two modification sites in each H3 histone, one which may have an active mark (such as H3K4me3) and the other which may have a repressive mark (such as H3K27me3). Thus, there are 16 possible states of a nucleosome, and each of which is determined by 4 histone modification sites (see Figure S1). As shown in Text S1, this, together with the restriction obtained from experiment [30] that active and repressive marks do not occur simultaneously on the same H3 histone, leads to the six physically distinct nucleosome states depicted in Fig. 1. In Fig. 1 the circle represents a nucleosome and the vertical ellipses represent H3 histones. The lower case letters within each ellipse represent the states of the two modification sites of the H3 histone ( = unmodified,  = modified by an active mark,  = modified by a repressive mark). For convenience, we assign the symbols , , , , , and to the six possible states. From now on, when we say ‘histone’ it is to be understood that we mean an H3 histone. We note that the state will play a prominent role in subsequent considerations in the Results section, and we will call a nucleosome in this state a ‘bivalent nucleosome’.


Modeling the dynamics of bivalent histone modifications.

Ku WL, Girvan M, Yuan GC, Sorrentino F, Ott E - PLoS ONE (2013)

6-state model.Illustration of the states in the 6-state model. Circles represent nucleosomes. A nucleosome contains two histones copies represented by the vertically oriented ellipses. Each histone has two sites, one site (represented by the upper half of the ellipse) that can be either unmodified (symbolized by ) or have an active mark (symbolized by ), and another site (represented by the lower half of the ellipse) that can be either unmodified (symbolized by ) or have a repressive mark (symbolized by ). (Note that the physical nucleosome states labeled ,  and  could be just as well depicted by interchanging the left and right ellipses within the respective circles.).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3815350&req=5

pone-0077944-g001: 6-state model.Illustration of the states in the 6-state model. Circles represent nucleosomes. A nucleosome contains two histones copies represented by the vertically oriented ellipses. Each histone has two sites, one site (represented by the upper half of the ellipse) that can be either unmodified (symbolized by ) or have an active mark (symbolized by ), and another site (represented by the lower half of the ellipse) that can be either unmodified (symbolized by ) or have a repressive mark (symbolized by ). (Note that the physical nucleosome states labeled , and could be just as well depicted by interchanging the left and right ellipses within the respective circles.).
Mentions: We consider a 1D lattice of nucleosomes, where there is a nucleosome at each lattice site . An actual nucleosome consists of 8 histone protein molecules, that can be regarded as two identical groups of four each. In what follows we only consider the state of one of these four histone group members, namely the H3 histone, which is specifically related to bivalency. Thus, in our model, we represent the state of a nucleosome as being determined by the states of its two H3 histone copies. There are two modification sites in each H3 histone, one which may have an active mark (such as H3K4me3) and the other which may have a repressive mark (such as H3K27me3). Thus, there are 16 possible states of a nucleosome, and each of which is determined by 4 histone modification sites (see Figure S1). As shown in Text S1, this, together with the restriction obtained from experiment [30] that active and repressive marks do not occur simultaneously on the same H3 histone, leads to the six physically distinct nucleosome states depicted in Fig. 1. In Fig. 1 the circle represents a nucleosome and the vertical ellipses represent H3 histones. The lower case letters within each ellipse represent the states of the two modification sites of the H3 histone ( = unmodified,  = modified by an active mark,  = modified by a repressive mark). For convenience, we assign the symbols , , , , , and to the six possible states. From now on, when we say ‘histone’ it is to be understood that we mean an H3 histone. We note that the state will play a prominent role in subsequent considerations in the Results section, and we will call a nucleosome in this state a ‘bivalent nucleosome’.

Bottom Line: It is generally agreed that bivalent domains play an important role in stem cell differentiation, but the underlying mechanisms remain unclear.Here we formulate a mathematical model to investigate the dynamic properties of histone modification patterns.We then illustrate that our modeling framework can be used to capture key features of experimentally observed combinatorial chromatin states.

View Article: PubMed Central - PubMed

Affiliation: Department of Physics, University of Maryland, College Park, Maryland, United States of America ; Institute for Research in Electronics and Applied Physics, University of Maryland, College Park, Maryland, United States of America.

ABSTRACT
Epigenetic modifications to histones may promote either activation or repression of the transcription of nearby genes. Recent experimental studies show that the promoters of many lineage-control genes in stem cells have "bivalent domains" in which the nucleosomes contain both active (H3K4me3) and repressive (H3K27me3) marks. It is generally agreed that bivalent domains play an important role in stem cell differentiation, but the underlying mechanisms remain unclear. Here we formulate a mathematical model to investigate the dynamic properties of histone modification patterns. We then illustrate that our modeling framework can be used to capture key features of experimentally observed combinatorial chromatin states.

Show MeSH