---
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abstract:
- lang: eng
text: "In the thesis we focus on the interplay of the biophysics and evolution of
gene regulation. We start by addressing how the type of prokaryotic gene regulation
– activation and repression – affects spurious binding to DNA, also known as\r\ntranscriptional
crosstalk. We propose that regulatory interference caused by excess regulatory
proteins in the dense cellular medium – global crosstalk – could be a factor in
determining which type of gene regulatory network is evolutionarily preferred.
Next,we use a normative approach in eukaryotic gene regulation to describe minimal\r\nnon-equilibrium
enhancer models that optimize so-called regulatory phenotypes. We find a class
of models that differ from standard thermodynamic equilibrium models by a single
parameter that notably increases the regulatory performance. Next chapter addresses
the question of genotype-phenotype-fitness maps of higher dimensional phenotypes.
We show that our biophysically realistic approach allows us to understand how
the mechanisms of promoter function constrain genotypephenotype maps, and how
they affect the evolutionary trajectories of promoters.\r\nIn the last chapter
we ask whether the intrinsic instability of gene duplication and amplification
provides a generic alternative to canonical gene regulation. Using mathematical
modeling, we show that amplifications can tune gene expression in many environments,
including those where transcription factor-based schemes are\r\nhard to evolve
or maintain. "
acknowledgement: For the duration of his PhD, Rok was a recipient of a DOC fellowship
of the Austrian Academy of Sciences.
alternative_title:
- ISTA Thesis
article_processing_charge: No
author:
- first_name: Rok
full_name: Grah, Rok
id: 483E70DE-F248-11E8-B48F-1D18A9856A87
last_name: Grah
orcid: 0000-0003-2539-3560
citation:
ama: Grah R. Gene regulation across scales – how biophysical constraints shape evolution.
2020. doi:10.15479/AT:ISTA:8155
apa: Grah, R. (2020). Gene regulation across scales – how biophysical constraints
shape evolution. Institute of Science and Technology Austria. https://doi.org/10.15479/AT:ISTA:8155
chicago: Grah, Rok. “Gene Regulation across Scales – How Biophysical Constraints
Shape Evolution.” Institute of Science and Technology Austria, 2020. https://doi.org/10.15479/AT:ISTA:8155.
ieee: R. Grah, “Gene regulation across scales – how biophysical constraints shape
evolution,” Institute of Science and Technology Austria, 2020.
ista: Grah R. 2020. Gene regulation across scales – how biophysical constraints
shape evolution. Institute of Science and Technology Austria.
mla: Grah, Rok. Gene Regulation across Scales – How Biophysical Constraints Shape
Evolution. Institute of Science and Technology Austria, 2020, doi:10.15479/AT:ISTA:8155.
short: R. Grah, Gene Regulation across Scales – How Biophysical Constraints Shape
Evolution, Institute of Science and Technology Austria, 2020.
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supervisor:
- first_name: Calin C
full_name: Guet, Calin C
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last_name: Guet
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full_name: Tkačik, Gašper
id: 3D494DCA-F248-11E8-B48F-1D18A9856A87
last_name: Tkačik
orcid: 0000-0002-6699-1455
title: Gene regulation across scales – how biophysical constraints shape evolution
type: dissertation
user_id: c635000d-4b10-11ee-a964-aac5a93f6ac1
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...
---
_id: '9000'
abstract:
- lang: eng
text: 'In prokaryotes, thermodynamic models of gene regulation provide a highly
quantitative mapping from promoter sequences to gene-expression levels that is
compatible with in vivo and in vitro biophysical measurements. Such concordance
has not been achieved for models of enhancer function in eukaryotes. In equilibrium
models, it is difficult to reconcile the reported short transcription factor (TF)
residence times on the DNA with the high specificity of regulation. In nonequilibrium
models, progress is difficult due to an explosion in the number of parameters.
Here, we navigate this complexity by looking for minimal nonequilibrium enhancer
models that yield desired regulatory phenotypes: low TF residence time, high specificity,
and tunable cooperativity. We find that a single extra parameter, interpretable
as the “linking rate,” by which bound TFs interact with Mediator components, enables
our models to escape equilibrium bounds and access optimal regulatory phenotypes,
while remaining consistent with the reported phenomenology and simple enough to
be inferred from upcoming experiments. We further find that high specificity in
nonequilibrium models is in a trade-off with gene-expression noise, predicting
bursty dynamics—an experimentally observed hallmark of eukaryotic transcription.
By drastically reducing the vast parameter space of nonequilibrium enhancer models
to a much smaller subspace that optimally realizes biological function, we deliver
a rich class of models that could be tractably inferred from data in the near
future.'
acknowledgement: G.T. was supported by Human Frontiers Science Program Grant RGP0034/2018.
R.G. was supported by the Austrian Academy of Sciences DOC Fellowship. R.G. thanks
S. Avvakumov for helpful discussions.
article_processing_charge: No
article_type: original
author:
- first_name: Rok
full_name: Grah, Rok
id: 483E70DE-F248-11E8-B48F-1D18A9856A87
last_name: Grah
orcid: 0000-0003-2539-3560
- first_name: Benjamin
full_name: Zoller, Benjamin
last_name: Zoller
- first_name: Gašper
full_name: Tkačik, Gašper
id: 3D494DCA-F248-11E8-B48F-1D18A9856A87
last_name: Tkačik
orcid: 0000-0002-6699-1455
citation:
ama: Grah R, Zoller B, Tkačik G. Nonequilibrium models of optimal enhancer function.
PNAS. 2020;117(50):31614-31622. doi:10.1073/pnas.2006731117
apa: Grah, R., Zoller, B., & Tkačik, G. (2020). Nonequilibrium models of optimal
enhancer function. PNAS. National Academy of Sciences. https://doi.org/10.1073/pnas.2006731117
chicago: Grah, Rok, Benjamin Zoller, and Gašper Tkačik. “Nonequilibrium Models of
Optimal Enhancer Function.” PNAS. National Academy of Sciences, 2020. https://doi.org/10.1073/pnas.2006731117.
ieee: R. Grah, B. Zoller, and G. Tkačik, “Nonequilibrium models of optimal enhancer
function,” PNAS, vol. 117, no. 50. National Academy of Sciences, pp. 31614–31622,
2020.
ista: Grah R, Zoller B, Tkačik G. 2020. Nonequilibrium models of optimal enhancer
function. PNAS. 117(50), 31614–31622.
mla: Grah, Rok, et al. “Nonequilibrium Models of Optimal Enhancer Function.” PNAS,
vol. 117, no. 50, National Academy of Sciences, 2020, pp. 31614–22, doi:10.1073/pnas.2006731117.
short: R. Grah, B. Zoller, G. Tkačik, PNAS 117 (2020) 31614–31622.
date_created: 2021-01-10T23:01:17Z
date_published: 2020-12-15T00:00:00Z
date_updated: 2023-08-24T11:10:22Z
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doi: 10.1073/pnas.2006731117
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grant_number: RGP0034/2018
name: Can evolution minimize spurious signaling crosstalk to reach optimal performance?
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name: Biophysically realistic genotype-phenotype maps for regulatory networks
publication: PNAS
publication_identifier:
eissn:
- '10916490'
issn:
- '00278424'
publication_status: published
publisher: National Academy of Sciences
quality_controlled: '1'
related_material:
link:
- description: News on IST Homepage
relation: press_release
url: https://ist.ac.at/en/news/new-compact-model-for-gene-regulation-in-higher-organisms/
scopus_import: '1'
status: public
title: Nonequilibrium models of optimal enhancer function
tmp:
image: /images/cc_by_nc_nd.png
legal_code_url: https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode
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_id: '7652'
abstract:
- lang: eng
text: Organisms cope with change by taking advantage of transcriptional regulators.
However, when faced with rare environments, the evolution of transcriptional regulators
and their promoters may be too slow. Here, we investigate whether the intrinsic
instability of gene duplication and amplification provides a generic alternative
to canonical gene regulation. Using real-time monitoring of gene-copy-number mutations
in Escherichia coli, we show that gene duplications and amplifications enable
adaptation to fluctuating environments by rapidly generating copy-number and,
therefore, expression-level polymorphisms. This amplification-mediated gene expression
tuning (AMGET) occurs on timescales that are similar to canonical gene regulation
and can respond to rapid environmental changes. Mathematical modelling shows that
amplifications also tune gene expression in stochastic environments in which transcription-factor-based
schemes are hard to evolve or maintain. The fleeting nature of gene amplifications
gives rise to a generic population-level mechanism that relies on genetic heterogeneity
to rapidly tune the expression of any gene, without leaving any genomic signature.
acknowledgement: We thank L. Hurst, N. Barton, M. Pleska, M. Steinrück, B. Kavcic
and A. Staron for input on the manuscript, and To. Bergmiller and R. Chait for help
with microfluidics experiments. I.T. is a recipient the OMV fellowship. R.G. is
a recipient of a DOC (Doctoral Fellowship Programme of the Austrian Academy of Sciences)
Fellowship of the Austrian Academy of Sciences.
article_processing_charge: No
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author:
- first_name: Isabella
full_name: Tomanek, Isabella
id: 3981F020-F248-11E8-B48F-1D18A9856A87
last_name: Tomanek
orcid: 0000-0001-6197-363X
- first_name: Rok
full_name: Grah, Rok
id: 483E70DE-F248-11E8-B48F-1D18A9856A87
last_name: Grah
orcid: 0000-0003-2539-3560
- first_name: M.
full_name: Lagator, M.
last_name: Lagator
- first_name: A. M. C.
full_name: Andersson, A. M. C.
last_name: Andersson
- first_name: Jonathan P
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last_name: Tkačik
orcid: 0000-0002-6699-1455
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full_name: Guet, Calin C
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last_name: Guet
orcid: 0000-0001-6220-2052
citation:
ama: Tomanek I, Grah R, Lagator M, et al. Gene amplification as a form of population-level
gene expression regulation. Nature Ecology & Evolution. 2020;4(4):612-625.
doi:10.1038/s41559-020-1132-7
apa: Tomanek, I., Grah, R., Lagator, M., Andersson, A. M. C., Bollback, J. P., Tkačik,
G., & Guet, C. C. (2020). Gene amplification as a form of population-level
gene expression regulation. Nature Ecology & Evolution. Springer Nature.
https://doi.org/10.1038/s41559-020-1132-7
chicago: Tomanek, Isabella, Rok Grah, M. Lagator, A. M. C. Andersson, Jonathan P
Bollback, Gašper Tkačik, and Calin C Guet. “Gene Amplification as a Form of Population-Level
Gene Expression Regulation.” Nature Ecology & Evolution. Springer Nature,
2020. https://doi.org/10.1038/s41559-020-1132-7.
ieee: I. Tomanek et al., “Gene amplification as a form of population-level
gene expression regulation,” Nature Ecology & Evolution, vol. 4, no.
4. Springer Nature, pp. 612–625, 2020.
ista: Tomanek I, Grah R, Lagator M, Andersson AMC, Bollback JP, Tkačik G, Guet CC.
2020. Gene amplification as a form of population-level gene expression regulation.
Nature Ecology & Evolution. 4(4), 612–625.
mla: Tomanek, Isabella, et al. “Gene Amplification as a Form of Population-Level
Gene Expression Regulation.” Nature Ecology & Evolution, vol. 4, no.
4, Springer Nature, 2020, pp. 612–25, doi:10.1038/s41559-020-1132-7.
short: I. Tomanek, R. Grah, M. Lagator, A.M.C. Andersson, J.P. Bollback, G. Tkačik,
C.C. Guet, Nature Ecology & Evolution 4 (2020) 612–625.
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date_published: 2020-04-01T00:00:00Z
date_updated: 2024-03-25T23:30:20Z
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ddc:
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department:
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- _id: CaGu
doi: 10.1038/s41559-020-1132-7
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...
---
_id: '7675'
abstract:
- lang: eng
text: 'In prokaryotes, thermodynamic models of gene regulation provide a highly
quantitative mapping from promoter sequences to gene expression levels that is
compatible with in vivo and in vitro bio-physical measurements. Such concordance
has not been achieved for models of enhancer function in eukaryotes. In equilibrium
models, it is difficult to reconcile the reported short transcription factor (TF)
residence times on the DNA with the high specificity of regulation. In non-equilibrium
models, progress is difficult due to an explosion in the number of parameters.
Here, we navigate this complexity by looking for minimal non-equilibrium enhancer
models that yield desired regulatory phenotypes: low TF residence time, high specificity
and tunable cooperativity. We find that a single extra parameter, interpretable
as the “linking rate” by which bound TFs interact with Mediator components, enables
our models to escape equilibrium bounds and access optimal regulatory phenotypes,
while remaining consistent with the reported phenomenology and simple enough to
be inferred from upcoming experiments. We further find that high specificity in
non-equilibrium models is in a tradeoff with gene expression noise, predicting
bursty dynamics — an experimentally-observed hallmark of eukaryotic transcription.
By drastically reducing the vast parameter space to a much smaller subspace that
optimally realizes biological function prior to inference from data, our normative
approach holds promise for mathematical models in systems biology.'
article_processing_charge: No
author:
- first_name: Rok
full_name: Grah, Rok
id: 483E70DE-F248-11E8-B48F-1D18A9856A87
last_name: Grah
orcid: 0000-0003-2539-3560
- first_name: Benjamin
full_name: Zoller, Benjamin
last_name: Zoller
- first_name: Gašper
full_name: Tkačik, Gašper
id: 3D494DCA-F248-11E8-B48F-1D18A9856A87
last_name: Tkačik
orcid: 0000-0002-6699-1455
citation:
ama: Grah R, Zoller B, Tkačik G. Normative models of enhancer function. bioRxiv.
2020. doi:10.1101/2020.04.08.029405
apa: Grah, R., Zoller, B., & Tkačik, G. (2020). Normative models of enhancer
function. bioRxiv. Cold Spring Harbor Laboratory. https://doi.org/10.1101/2020.04.08.029405
chicago: Grah, Rok, Benjamin Zoller, and Gašper Tkačik. “Normative Models of Enhancer
Function.” BioRxiv. Cold Spring Harbor Laboratory, 2020. https://doi.org/10.1101/2020.04.08.029405.
ieee: R. Grah, B. Zoller, and G. Tkačik, “Normative models of enhancer function,”
bioRxiv. Cold Spring Harbor Laboratory, 2020.
ista: Grah R, Zoller B, Tkačik G. 2020. Normative models of enhancer function. bioRxiv,
10.1101/2020.04.08.029405.
mla: Grah, Rok, et al. “Normative Models of Enhancer Function.” BioRxiv,
Cold Spring Harbor Laboratory, 2020, doi:10.1101/2020.04.08.029405.
short: R. Grah, B. Zoller, G. Tkačik, BioRxiv (2020).
date_created: 2020-04-23T10:12:51Z
date_published: 2020-04-09T00:00:00Z
date_updated: 2023-09-07T13:13:26Z
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