We introduce and analyze a minimal model of epigenetic silencing in budding yeast, built only uponknown biomolecular interactions in the system ,a posteriori identifying the key ones necessary for 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. More remarkably, besides the silenced and transcriptionally active fate of chromatin, our model leads to a novel state with bivalent  marks under certain perturbations (knock-out mutations, inhibition or enhancement of enzymatic activity). The bivalent state  is shown to result in patchy silencing in regions of parameter space and turns out to be pertinent in several perturbations . 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 helping clarify disparate experimental observations in the literature within an unified theoretical frameworkfor the first time and leading to fresh experimental proposals . Specifically, we discuss the behavior of Sir protein recruitment, spreading and stability of silenced regions in commonly-studied mutants (e.g., \emph{sas2}%DIFAUXCMD %DIFDELCMD < \varDelta%%% ,\emph{dot1}%DIFAUXCMD %DIFDELCMD < \varDelta%%%  ) illuminating the controversial role of Dot1 in the systems biology of yeast silencing.
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., \emph{}%DIFAUXCMD %DIFDELCMD < \varDelta%%% \emph{}%DIFAUXCMD %DIFDELCMD < \varDelta%%% sas2, dot1 ) illuminating the controversial role of Dot1 in the systems biology of yeast silencing.
D
only upon
R
known
upon known
D
,
D
a posteriori
R
identifying the key ones necessary for
. Doing so, we identify the epigenetic marks essential for the
D
,
R
More remarkably, besides
Besides
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(i.e., both active and silencing)
A
appears under several perturbations and
D
in regions of parameter space and turns out to be pertinent in several perturbations
R
helping clarify
and
R
in the literature within an unified theoretical frameworkfor the first time and leading to fresh experimental proposals
are assessed within a single theoretical framework
D
sas2
D
,
D
dot1
A
sas2, dot1