Analytical and computational study of the stochastic behavior of a chromatin modification circuit
Author(s)
Bruno, Simone; Williams, Ruth J.; Del Vecchio, Domitilla
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— The property of multicellular organisms that
allows cells with the same genetic code to maintain distinct
identities for the entire life of the organism is known
as epigenetic cell memory (ECM). Recently, chromatin
modifications and their effect on the DNA structure, that
is, the chromatin state, have appeared to have a key role
in ECM. Here, we conduct a stochastic analysis of a
chromatin modification circuit to determine the effect of
time scale separation among key constituent processes on
the extent to which the system can keep a stable steady
state in the face of noise. Specifically, from the full set of
reactions describing the system, we first obtain a reduced
circuit model and determine an analytical expression for
both the system stationary probability distribution and the
switching time between repressed and active chromatin
states. Then, we validate these analytical results with
stochastic simulations of the original full set of reactions.
Our results show that when the basal decay of all chromatin marks is sufficiently slower with respect to the
speed of auto and cross-catalysis and of the recruited
erasure of all the marks, the stationary distribution shows
bimodality, with two concentrated peaks in correspondence
of the active and repressed states, but biased towards the
repressed state. In accordance with these results, slower
basal decay increases the extent of memory of the active
and repressed states, suggesting, more broadly, a critical
design principle for long-term memory of gene expression
states.
Description
2022 IEEE 61st Conference on Decision and Control (CDC) December 6-9, 2022. Cancún, Mexico
Date issued
2022-12-06Department
Massachusetts Institute of Technology. Department of Mechanical EngineeringPublisher
IEEE|2022 IEEE 61st Conference on Decision and Control (CDC)
Citation
Bruno, Simone, Williams, Ruth J. and Del Vecchio, Domitilla. 2022. "Analytical and computational study of the stochastic behavior of a chromatin modification circuit."
Version: Author's final manuscript