PLOS ONE Modeling the Dynamics of Bivalent Histone Modifications — Volkswagen Polo Lim

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Modeling the Dynamics of Bivalent Modifications

Affiliations: Department of University of Maryland, College Maryland, United States of Institute for Research in Electronics and Physics, University of Maryland, Park, Maryland, United of America

Michelle Girvan,

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

Ku WL, Girvan M, Yuan G-C, F, Ott E (2013) Modeling the Dynamics of Histone Modifications. PLoS ONE e77944. doi:10.1371/journal.pone.0077944

Editor: Jordi Garcia-Ojalvo, Politecnica de Catalunya, Spain

June 13, 2013; Accepted: 5, 2013; Published: November 1,

Copyright: © 2013 Ku et al. This is an article distributed under the of the Creative Commons Attribution which permits unrestricted distribution, and reproduction in any medium, the original author and source are

Funding: This work was by Office of Naval Research N000140710734 and United States Institutes of Health grant The funders had no role in study data collection and analysis, to publish, or preparation of the manuscript.

interests: The authors have that no competing interests

Introduction

Histones can undergo types of covalent modifications, as methylation and acetylation, which as an additional layer of transcriptional by mediating the chromatin accessibility and by regulatory proteins [1]. Experimental studies using immunoprecipitation followed by massively sequencing (ChIP-seq) have that different cell can be characterized by different histone patterns [3] .

The molecular mechanisms underlying state establishment, maintenance, and remain incompletely understood. A of mechanisms are implicated [4]. (1) sequence-specific recruitment through between chromatin regulators and DNA factors; (2) recruitment of chromatin to existing histone marks; (3) marks deposited by transcriptional (4) RNA mediated recruitment; and (5) stochasticity with DNA replication. However, any mechanism alone is insufficient for state establishment [4]. [5] .


One of the characterized chromatin states is a domain, a segment of the nucleosome in which H3K4me3 (an active and H3K27me3 (a repressive mark) on most individual nucleosomes the domain [6]. Bivalent are thought to be an important feature of cells. For example, bivalent have been discovered in the of most lineage-control genes in stem cells, and most of domains become monovalent cell differentiation [3]. [6] Also, a recent study that gene activation in the process occurs in conjunction the decay of repressive marks in domains [10]. In particular, one proposal [6] for the function of bivalent is that the H3K27me3 marks act to the lineage-control gene in stem while the H3K4me3 marks these genes for activation cell differentiation. Thus proposal suggests that of these genes in differentiated is determined by the existence of bivalent in stem cells. These indicate the importance of bivalent and motivate further study in to illuminate the underlying principles and involved in their formation and

It has been proposed that the of chromatin domains is consistent a model that includes not the chemical interactions between marks, but also nucleation where domains are more to form [11]. The dynamics of modifications have been both theoretically and experimentally for time [11] –[15]. In histone methylation marks are by a variety of methyltransferase enzymes may act singly or cooperatively. For example, marks are catalyzed by Ezh2, a member of the Polycomb group In addition to the normal stochastic which would be expected each of these individual there is also a feedback between the histone marks and the [16]. Existing H3K27me3 may attract Polycomb group which enhance nearby [17]. [18]. A similar mechanism has also been for H3K4me3 via Trithorax protein (TrxG) [19]. In addition, exists experimental evidence a negative feedback mechanism H3K4me3 and H3K27me3 marks via the of histone demethylases[20] –[24] .

Certain specific DNA sequences may as the docking sites of modification and may therefore be associated with local attraction of histone [4]. [25]. We refer to as nucleation sites. For example, CpG are strongly enriched in bivalent in human and mouse embryonic cells [19]. and appear to be for Polycomb binding in certain [26] .

Recently, in silico methods provided important additional for chromatin state inheritance. contributions have been by Dodd el al. [12] and Sedighi and [27]. These paper 1-dimensional lattice models in nucleosomes are allowed to have or repressive modifications that stochastically and by recruitment. They that a bistable state either mostly active or mostly repressive nucleosomes can and be heritable, consistent with observations. Subsequently, Hodges and [11] found that a nucleation site into a of the above type produces a chromatin domain. Also, in a recent paper, Binder et al. proposed a model describing of catalytic enzymes to DNA and their with histone marks one aim being explaining length of modified chromatin regions. past studies are limited to a type of histone mark on a whereas it is well-known that regulation is governed by combinatorial of multiple histone marks [29]. In this paper, we previous studies by presenting an to model the dynamics of combinatorial states. This is achieved by each individual nucleosome to both active and repressive simultaneously.

In the next section we describe our Then, in the Results section, we this model to investigate the of histone modification patterns the focus on bivalent domains. and Conclusions are given at the end of the paper.

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