While the steady-state behavior of stochastic gene expression with auto-regulation has been extensively studied, its time-dependent behavior has received much less attention. Here, under the assumption of fast promoter switching, we derive and solve a reduced chemical master equation for an auto-regulatory gene circuit with translational bursting and cooperative protein-gene interactions. The analytical expression for the time-dependent probability distribution of protein numbers enables a fast exploration of large swaths of the parameter space. For a unimodal initial distribution, we identify three distinct types of stochastic dynamics: (i) the protein distribution remains unimodal at all times; (ii) the protein distribution becomes bimodal at intermediate times and then reverts back to being unimodal at long times (transient bimodality); and (iii) the protein distribution switches to being bimodal at long times. For each of these, the deterministic model predicts either monostable or bistable behavior, and hence, there exist six dynamical phases in total. We investigate the relationship of the six phases to the transcription rates, the protein binding and unbinding rates, the mean protein burst size, the degree of cooperativity, the relaxation time to the steady state, the protein mean, and the type of feedback loop (positive or negative). We show that transient bimodality is a noise-induced phenomenon that occurs when the protein expression is sufficiently bursty, and we use a theory to estimate the observation time window when it is manifested.

1.
S. S.
Shen-Orr
,
R.
Milo
,
S.
Mangan
, and
U.
Alon
, “
Network motifs in the transcriptional regulation network of Escherichia coli
,”
Nat. Gen.
31
,
64
68
(
2002
).
2.
N.
Rosenfeld
,
M. B.
Elowitz
, and
U.
Alon
, “
Negative autoregulation speeds the response times of transcription networks
,”
J. Mol. Biol.
323
,
785
793
(
2002
).
3.
A.
Becskei
and
L.
Serrano
, “
Engineering stability in gene networks by autoregulation
,”
Nature
405
,
590
593
(
2000
).
4.
D. W.
Austin
 et al, “
Gene network shaping of inherent noise spectra
,”
Nature
439
,
608
611
(
2006
).
5.
Y.
Dublanche
,
K.
Michalodimitrakis
,
N.
Kümmerer
,
M.
Foglierini
, and
L.
Serrano
, “
Noise in transcription negative feedback loops: Simulation and experimental analysis
,”
Mol. Syst. Biol.
2
,
41
(
2006
).
6.
J.
Hornos
 et al, “
Self-regulating gene: An exact solution
,”
Phys. Rev. E
72
,
051907
(
2005
).
7.
N.
Kumar
,
T.
Platini
, and
R. V.
Kulkarni
, “
Exact distributions for stochastic gene expression models with bursting and feedback
,”
Phys. Rev. Lett.
113
,
268105
(
2014
).
8.
R.
Grima
,
D. R.
Schmidt
, and
T. J.
Newman
, “
Steady-state fluctuations of a genetic feedback loop: An exact solution
,”
J. Chem. Phys.
137
,
035104
(
2012
).
9.
C.
Jia
and
R.
Grima
, “
Small protein number effects in stochastic models of autoregulated bursty gene expression
,”
J. Chem. Phys.
152
,
084115
(
2020
).
10.
C.
Gardiner
,
Stochastic Methods
(
Springer Berlin
,
2009
), Vol. 4.
11.
A.
Grönlund
,
P.
Lötstedt
, and
J.
Elf
, “
Transcription factor binding kinetics constrain noise suppression via negative feedback
,”
Nat. Commun.
4
,
1864
(
2013
).
12.
J.
Holehouse
,
Z.
Cao
, and
R.
Grima
, “
Stochastic modeling of auto-regulatory genetic feedback loops: A review and comparative study
,”
Biophys. J.
118
,
1517
(
2020
).
13.
P.
Kurasov
,
A.
Lück
,
D.
Mugnolo
, and
V.
Wolf
, “
Stochastic hybrid models of gene regulatory networks–a pde approach
,”
Math. Biosci.
305
,
170
177
(
2018
).
14.
Z.
Cao
and
R.
Grima
, “
Linear mapping approximation of gene regulatory networks with stochastic dynamics
,”
Nat. Commun.
9
,
3305
(
2018
).
15.
L.
Ham
,
D.
Schnoerr
,
R. D.
Brackston
, and
M. P.
Stumpf
, “
Exactly solvable models of stochastic gene expression
,”
J. Chem. Phys.
152
,
144106
(
2020
).
16.
D. F.
Anderson
,
D.
Schnoerr
, and
C.
Yuan
, “
Time-dependent product-form Poisson distributions for reaction networks with higher order complexes
,”
J. Math. Biol.
(published online).
17.
A. F.
Ramos
,
G.
Innocentini
, and
J. E. M.
Hornos
, “
Exact time-dependent solutions for a self-regulating gene
,”
Phys. Rev. E
83
,
062902
(
2011
).
18.
Z.
Cao
and
R.
Grima
, “
Analytical distributions for detailed models of stochastic gene expression in eukaryotic cells
,”
Proc. Natl. Acad. Sci. U. S. A.
117
,
4682
4692
(
2020
).
19.
F.
Veerman
,
C.
Marr
, and
N.
Popović
, “
Time-dependent propagators for stochastic models of gene expression: An analytical method
,”
J. Math. Biol.
77
,
261
312
(
2018
).
20.
N.
Friedman
,
L.
Cai
, and
X. S.
Xie
, “
Linking stochastic dynamics to population distribution: An analytical framework of gene expression
,”
Phys. Rev. Lett.
97
,
168302
(
2006
).
21.
J.
Yu
,
J.
Xiao
,
X.
Ren
,
K.
Lao
, and
X. S.
Xie
, “
Probing gene expression in live cells, one protein molecule at a time
,”
Science
311
,
1600
1603
(
2006
).
22.
L.
Cai
,
N.
Friedman
, and
X. S.
Xie
, “
Stochastic protein expression in individual cells at the single molecule level
,”
Nature
440
,
358
362
(
2006
).
23.
P.
Bokes
,
J. R.
King
,
A. T. A.
Wood
, and
M.
Loose
, “
Multiscale stochastic modelling of gene expression
,”
J. Math. Biol.
65
,
493
520
(
2012
).
24.
C.
Jia
, “
Simplification of Markov chains with infinite state space and the mathematical theory of random gene expression bursts
,”
Phys. Rev. E
96
,
032402
(
2017
).
25.
C.
Jia
,
P.
Xie
,
M.
Chen
, and
M. Q.
Zhang
, “
Stochastic fluctuations can reveal the feedback signs of gene regulatory networks at the single-molecule level
,”
Sci. Rep.
7
,
16037
(
2017
).
26.
J.
Holehouse
and
R.
Grima
, “
Revisiting the reduction of stochastic models of genetic feedback loops with fast promoter switching
,”
Biophys. J.
117
,
1311
(
2019
).
27.
L. A.
Sepúlveda
,
H.
Xu
,
J.
Zhang
,
M.
Wang
, and
I.
Golding
, “
Measurement of gene regulation in individual cells reveals rapid switching between promoter states
,”
Science
351
,
1218
1222
(
2016
).
28.
S.
Bo
and
A.
Celani
, “
Multiple-scale stochastic processes: Decimation, averaging and beyond
,”
Phys. Rep.
670
,
1
59
(
2016
).
29.
C.
Jia
, “
Model simplification and loss of irreversibility
,”
Phys. Rev. E
93
,
052149
(
2016
).
30.
Z.
Wang
,
Z.
Zhang
, and
T.
Zhou
, “
Exact distributions for stochastic models of gene expression with arbitrary regulation
,”
Sci. Chin. Math.
63
,
485
500
(
2019
).
31.
P.
Bokes
and
J. R.
King
, “
Limit-cycle oscillatory coexpression of cross-inhibitory transcription factors: A model mechanism for lineage promiscuity
,”
Math. Med. Biol.: J. IMA
36
,
113
137
(
2019
).
32.
B.
Munsky
and
M.
Khammash
, “
The finite state projection algorithm for the solution of the chemical master equation
,”
J. Chem. Phys.
124
,
044104
(
2006
).
33.
G. G.
Yin
and
Q.
Zhang
,
Continuous-time Markov Chains and Applications: A Two-Time-Scale Approach
, 2nd ed. (
Springer
,
New York
,
2013
).
34.
C.
Jia
, “
Reduction of Markov chains with two-time-scale state transitions
,”
Stochastics
88
,
73
105
(
2016
).
35.
S.
Smith
and
V.
Shahrezaei
, “
General transient solution of the one-step master equation in one dimension
,”
Phys. Rev. E
91
,
062119
(
2015
).
36.
Higham
,
N. J.
Functions of Matrices: Theory and Computation
(
SIAM
,
2008
), Vol. 104.
37.
A.
Berman
and
R. J.
Plemmons
,
Nonnegative Matrices in the Mathematical Sciences
(
Academic Press
,
New York
,
1979
).
38.
A. D.
McNaught
,
A.
Wilkinson
 et al,
Compendium of Chemical Terminology
(
Blackwell Science Oxford
,
1997
), Vol. 1669.
39.
C.
Jia
,
H.
Qian
,
M.
Chen
, and
M. Q.
Zhang
, “
Relaxation rates of gene expression kinetics reveal the feedback signs of autoregulatory gene networks
,”
J. Chem. Phys.
148
,
095102
(
2018
).
40.
P.
Thomas
,
N.
Popovic
, and
R.
Grima
, “
Phenotypic switching in gene regulatory networks
,”
Proc. Natl. Acad. Sci. U. S. A.
111
,
6994
6999
(
2014
).
41.
D. R.
Larson
,
R. H.
Singer
, and
D.
Zenklusen
, “
A single molecule view of gene expression
,”
Trends Cell Biol.
19
,
630
637
(
2009
).
42.
B.
Schwanhäusser
 et al, “
Global quantification of mammalian gene expression control
,”
Nature
473
,
337
(
2011
).
43.
C. H. L.
Beentjes
,
R.
Perez-Carrasco
, and
R.
Grima
, “
Exact solution of stochastic gene expression models with bursting, cell cycle and replication dynamics
,”
Phys. Rev. E
101
,
032403
(
2020
).
44.
M.-F.
Chen
,
Eigenvalues, Inequalities, and Ergodic Theory
(
Springer
,
2006
).
You do not currently have access to this content.