Toward principles of gene regulation in multicellular systems?

Date:
July 1, 2020
Source:
Northwestern University
Summary:
Quantitative biologists ombine precision measurements and
mathematical models to uncover a common mechanism regulating gene
expression during development.



FULL STORY ==========================================================================
A team of quantitative biology researchers from Northwestern University
have uncovered new insights into the impact of stochasticity in gene expression, offering new evolutionary clues into organismal design
principles in the face of physical constraints.


==========================================================================
In cells, genes are expressed through transcription, a process
where genetic information encoded in DNA is copied into messenger
RNA (mRNA). The mRNA is then translated to make protein molecules,
the workhorses of cells. This entire process is subject to bursts of
natural stochasticity -- or randomness -- which can impact the outcome
of biological processes that proteins carry out.

The researchers' new experimental and theoretical analyses studied
a collection of genes in Drosophila, a family of fruit flies, and
found that gene expression is regulated by the frequency of these transcriptional bursts.

"It has been known for almost two decades that protein levels can
demonstrate large levels of stochasticity owing to their small numbers,
but this has never been empirically demonstrated in multicellular
organisms during the course of their development," said Madhav Mani,
assistant professor of engineering sciences and applied mathematics
at the McCormick School of Engineering. "This work for the first
time identifies the role of randomness in altering the outcome of a developmental process." A paper outlining the work, titled "The Wg and
Dpp Morphogens Regulate Gene Expression by Modulating the Frequency of Transcriptional Bursts," was published June 22 in the journal eLife. Mani
is a co-corresponding author on the study along with Richard Carthew,
professor of molecular biosciences in the Weinberg College of Arts and Sciences. Both are members of Northwestern's NSF- Simons Center for Quantitative Biology, which brings together mathematical scientists and developmental biologists to investigate the biology of animal development.

This study builds upon a recent paper in which the researchers studied
the role of stochastic gene expression on sensory pattern formation in Drosophila. By analyzing experimental perturbations of Drosophila's
senseless gene against mathematical models, the team determined the
sources of the gene's stochasticity, and found that the randomness appears
to be leveraged in order to accurately determine sensory neuron fates.



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The researchers applied that understanding to this latest study using
a technique called single molecule fluorescence in situ hybridization
(smFISH) to measure nascent and mature mRNA in genes downstream of two
key patterning factors, Wg and Dpp, responsible for the organ development
of fruit fly wings.

In comparing the measurements to their data models, the researchers
found that, while each gene's pattern of expression is unique, the
mechanism by which expression is regulated -- which the team named
"burst frequency modulation" - - is the same.

"Our results show that proteins' levels of randomness are impacted by
the physical structure of the genome surrounding the gene of interest
by modulating the features of the 'software' that control the levels of
gene expression," Mani said. "We developed an experimental approach to
study a large collection of genes in order to discern overall trends as
to how the stochastic software of gene regulation is itself regulated."
The observed patterns of gene regulation, Mani said, works like a
stochastic light switch.

"Let's say you are quickly flipping a light switch on and off, but you
want more brightness out of your bulb. You could either get a brighter
bulb that produced more photons per unit time, or you could leave the
switch 'on' more than 'off,'" Mani said. "What we found is that organisms control the amount of gene expression by regulating how often the gene
is permitted to switch on, rather than making more mRNAs when it is on." Carthew, director of the Center for Quantitative Biology, added that
this mode of gene expression regulation was observed for multiple genes,
which hints at the possibility of a broader biological principle where quantitative control of gene expression leverages the random nature of
the process.

"From these studies, we are learning rules for how genes can be made
more or less noisy," Carthew said. "Sometimes cells want to harness the
genetic noise - - the level of variation in gene expression -- to make randomized decisions.

Other times cells want to suppress the noise because it makes cells too variable for the good of the organism. Intrinsic features of a gene can
imbue them with more or less noise." While engineers are excited by
the ability to control and manipulate biological systems, Mani said,
more fundamental knowledge needs to be discovered.

"We only know the tip of the iceberg," Mani said. "We are far from a
time when basic science is considered complete and all that is left is engineering and design. The natural world is still hiding its deepest mysteries."

========================================================================== Story Source: Materials provided by Northwestern_University. Original
written by Alex Gerage.

Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Rachael Bakker, Madhav Mani, Richard W Carthew. The Wg and Dpp
morphogens
regulate gene expression by modulating the frequency of
transcriptional bursts. eLife, 2020; 9 DOI: 10.7554/eLife.56076 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/07/200701100027.htm

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