The role of multiple marks in epigenetic silencing and the emergence of a stable bivalent chromatin state

Mukhopadhyay, S., Sengupta, A. M. (2013) The role of multiple marks in epigenetic silencing and the emergence of a stable bivalent chromatin state. PLoS Computational Biology, 9 (7). e1003121. ISSN 1553-7358 (Electronic)1553-734X (Linking)

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URL: http://www.ncbi.nlm.nih.gov/pubmed/23874171
DOI: 10.1371/journal.pcbi.1003121

Abstract

We introduce and analyze a minimal model of epigenetic silencing in budding yeast, built upon known biomolecular interactions in the system. Doing so, we identify the epigenetic marks essential for the bistability of epigenetic states. The model explicitly incorporates two key chromatin marks, namely H4K16 acetylation and H3K79 methylation, and explores whether the presence of multiple marks lead to a qualitatively different systems behavior. We find that having both modifications is important for the robustness of epigenetic silencing. Besides the silenced and transcriptionally active fate of chromatin, our model leads to a novel state with bivalent (i.e., both active and silencing) marks under certain perturbations (knock-out mutations, inhibition or enhancement of enzymatic activity). The bivalent state appears under several perturbations and is shown to result in patchy silencing. We also show that the titration effect, owing to a limited supply of silencing proteins, can result in counter-intuitive responses. The design principles of the silencing system is systematically investigated and disparate experimental observations are assessed within a single theoretical framework. Specifically, we discuss the behavior of Sir protein recruitment, spreading and stability of silenced regions in commonly-studied mutants (e.g., sas2[Formula: see text], dot1[Formula: see text]) illuminating the controversial role of Dot1 in the systems biology of yeast silencing.

Item Type: Paper
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > Chromatin dynamics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > epigenetics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > epigenetics
CSHL Authors:
Communities: CSHL labs > Wigler lab
Depositing User: Matt Covey
Date Deposited: 26 Jul 2013 14:16
Last Modified: 16 Aug 2013 18:53
PMCID: PMC3715441
Related URLs:
URI: http://repository.cshl.edu/id/eprint/28470

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