How the motion of DNA controls gene activity

Date:
June 29, 2023
Source:
Institute of Science and Technology Austria
Summary:
Despite being densely packed to fit into the nucleus, chromosomes
storing our genetic information are always in motion. This allows
specific regions to come into contact and thereby activate a
gene. A group of scientists now visualized this dynamic process
and give novel insights into the physical characteristics of DNA.


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FULL STORY ========================================================================== Performing cutting-edge science requires thinking outside the box and
bringing together different scientific disciplines. Sometimes this even
means being in the right place at the right time. For David Bru"ckner, postdoctoral researcher and NOMIS fellow at ISTA, all the above-mentioned things came into effect as he attended an on-campus lecture by Professor
Thomas Gregor from Princeton University. Inspired by the talk, Bru"ckner reached out with an idea: to physically interpret the specific data sets
Gregor presented. Now, the results of their collaboration are published
in Science. They highlight the stochastic (random) motion of two specific
gene elements on a chromosome, which have to come into contact for the
gene to become active in 3D space.

How DNA fits into a cell nucleus Living organisms like humans are built
on genes that are stored in the DNA - - our molecular blueprint. DNA is
a polymer, a huge molecule of smaller individual parts (monomers). It
is located in every cell's nucleus. "Depending on the organism, the DNA
polymer can be up to meters long, yet the size of the nucleus is on the
order of microns," Bru"ckner explains. To fit into the tiny nucleus, DNA
gets compacted by being coiled as if on a spool and further compressed
into the well-known shape of chromosomes, which we all encountered in
a biology textbook.

"Despite being heavily condensed, chromosomes are not static; they are
jiggling around all the time," the physicist continues. These dynamics
are very important. Whenever a specific gene has to be activated, two
regions on the polymer called "enhancer" and "promoter" need to come into
close contact and bind to each other. Only when this happens, a cellular machinery reads off the gene's information and forms the RNA molecule,
which eventually gives rise to proteins that are essential for all the processes a living organism requires.

Depending on the organism, the enhancer and promoter can be quite far
from each other on the chromosome. "With previously used methods, you
could get a static view of the distance between these elements, but not
how the system evolves over time," Bru"ckner explains. Intrigued by this missing information, the scientists set out to get a dynamic look at how
these elements are organized and how they move in 3D space in real time.

Visualizing gene regions To achieve this goal, the experimental scientists
from Princeton established a method to track those two DNA elements over
a certain time period in a fly embryo. Through genetic manipulation,
the DNA elements were fluorescently labeled, with the enhancer region illuminating in green and the promoter in blue. Using live imaging
(time-lapse microscopy of living cells) the scientists were able to
visualize the fluorescent spots in fly embryos to see how they were
moving around to find each other.

Once the two spots came into proximity, the gene was activated and
an additional red light turned on as the RNA was also tagged with
red fluorophores. Bru"ckner excitedly adds, "We got a visual readout
of when the enhancer and promoter got in contact. That gave us a lot
of information about their trajectories." DNA is densely packed and
exhibits fast motion The challenge then was how to analyze this huge
data set of stochastic motion.

His background in theoretical physics allowed Bru"ckner to extract
statistics to understand the typical behavior of the system. He applied
two simplified, different physical models to cut through the data.

One was the Rouse model. It assumes that every monomer of the polymer is
an elastic spring. It predicts a loose structure and fast diffusion --
a random movement, where occasionally the gene regions encounter each
other. The other model is called the "fractal globule." It predicts
a very compact structure and therefore slow diffusion. "Surprisingly,
we found in the data that the system is described by a combination of
these two models -- a highly dense structure you would expect based
on the fractal globule model, and diffusion which is described by the statistics from the Rouse model," Bru"ckner explains.

Due to the combination of dense packing and fast motion, the binding
of these two gene regions depends much less on their distance along
the chromosome than previously anticipated. "If such a system is in a
fluid and dynamic state all the time, long-distance communication is
much better than we might have thought," Bru"ckner adds.

This study brings together the worlds of biology and physics. For
physicists, it is interesting, because the scientists tested the dynamics
of a complex biological system with physical theories that have been
around for a long time; and for biologists, it gives insights into the characteristics of a chromosome, which might help to understand gene interaction and gene activation in more detail.

* RELATED_TOPICS
o Health_&_Medicine
# Genes # Gene_Therapy # Human_Biology # Epigenetics
o Plants_&_Animals
# Genetics # Biochemistry_Research # Biotechnology #
Cell_Biology
* RELATED_TERMS
o Telomere o DNA_microarray o Genetics o DNA o Chromosome o
Meiosis o Allele o Gene

========================================================================== Story Source: Materials provided by Institute_of_Science_and_Technology_Austria. Note: Content may be edited
for style and length.


========================================================================== Journal Reference:
1. David B. Bru"ckner, Hongtao Chen, Lev Barinov, Benjamin Zoller,
Thomas
Gregor. Stochastic motion and transcriptional dynamics of pairs
of distal DNA loci on a compacted chromosome. Science, 2023; 380
(6652): 1357 DOI: 10.1126/science.adf5568 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2023/06/230629193228.htm

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