New compact model for gene regulation in higher organisms

December 03, 2020

Although the DNA and its double-helix are one of the most familiar molecules of our time, our knowledge of how cells control what genes they want to express still is rather limited. In order to create, for example, an enzyme, the information that's inscribed in our DNA about this enzyme needs to be transcribed and translated. To start this highly complex process special regulatory proteins called transcription factors (TFs) bind to specific DNA regions. That way, they can turn the expression of a gene on and off. The big question is: How can transcription factors find the right place on the DNA to properly regulate gene expression?

Simple model - big effect

For prokaryotes - simple cellular organisms without a nucleus, like bacteria - biophysical models already manage to predict gene expression based on the interaction between TFs and DNA regulatory regions. In prokaryotes, the TF binding sites on DNA are rather long and specific, making it easier for the TFs to find their target. In higher organisms called eukaryotes whose cells have a nucleus, mathematically describing the process of gene regulation proved to be much more difficult. Now, a team of researchers at the Institute of Science and Technology Austria (IST Austria) found a way to describe how the interaction between the different regulatory molecules in eukaryotes could look like.

In a new study published in PNAS, Rok Grah, a former graduate student at IST and now a data scientist, working with IST professor Gašper Tkačik and Benjamin Zoller from Princeton University proposed a minimal extension to a classic equilibrium model that can be applied to the switching between the active and inactive states of a gene. To this end, they selected a number of characteristics or "regulatory phenotypes" the desired model should satisfy. "We wanted a gene with a high specificity, meaning that the gene is activated only by the right TFs," says Rok Grah. Another regulatory phenotype included in the model was the TF residence time on a specific region and a random region of the DNA. "We were able to show that there is a class of simple models that perform well on all of these phenotypes, which wasn't done so far," explains Benjamin Zoller. Even though the proposed extension to classical model was minimal, it revealed a wealth of qualitatively new, non-equilibrium behaviors that are consistent with current experimental constraints.

Noisy genes

Based on existing data, the researchers argued that individual TFs are limited in their ability to differentiate between specific and random sites on the DNA. Therefore, although each type of TF preferentially binds certain regulatory DNA sequences, TFs bind other non-cognate targets, too. "The main motivation was to find a model to describe how the regulatory elements on the DNA don't get activated by non-cognate transcription factors," says Benjamin Zoller. Their findings suggest that high specificity of gene expression must be a collective effect of the regulatory molecules operating in the "proofreading regime".

Furthermore, if a gene is active, the number of proteins it produces fluctuates, creating what scientists call gene expression noise. "What surprised me was the tradeoff between noise and specificity. It seems like if you want to have high specificity, it tends to lead to more noise, which is intriguing," says Benjamin Zoller. High noise is often thought to be detrimental for cells, yet genes in eukaryotes are quite noisy. "So far, we don't really know why this whole transcription machinery has evolved that way. Perhaps an explanation is that high noise is unavoidable if you want high specificity. Within our model, there seems to be no way around it. High specificity will always mean high noise, and it is possible cells have evolved mechanisms to lower the noise later on in the gene expression process," adds Rok Grah. The next step in the collaboration is the experimental test of the new model. Its simplicity makes it perfectly suited for confrontation with precise real-time gene expression measurements, for example, on perturbed DNA regulatory sequences.

Institute of Science and Technology Austria

Related DNA Articles from Brightsurf:

A new twist on DNA origami
A team* of scientists from ASU and Shanghai Jiao Tong University (SJTU) led by Hao Yan, ASU's Milton Glick Professor in the School of Molecular Sciences, and director of the ASU Biodesign Institute's Center for Molecular Design and Biomimetics, has just announced the creation of a new type of meta-DNA structures that will open up the fields of optoelectronics (including information storage and encryption) as well as synthetic biology.

Solving a DNA mystery
''A watched pot never boils,'' as the saying goes, but that was not the case for UC Santa Barbara researchers watching a ''pot'' of liquids formed from DNA.

Junk DNA might be really, really useful for biocomputing
When you don't understand how things work, it's not unusual to think of them as just plain old junk.

Designing DNA from scratch: Engineering the functions of micrometer-sized DNA droplets
Scientists at Tokyo Institute of Technology (Tokyo Tech) have constructed ''DNA droplets'' comprising designed DNA nanostructures.

Does DNA in the water tell us how many fish are there?
Researchers have developed a new non-invasive method to count individual fish by measuring the concentration of environmental DNA in the water, which could be applied for quantitative monitoring of aquatic ecosystems.

Zigzag DNA
How the cell organizes DNA into tightly packed chromosomes. Nature publication by Delft University of Technology and EMBL Heidelberg.

Scientists now know what DNA's chaperone looks like
Researchers have discovered the structure of the FACT protein -- a mysterious protein central to the functioning of DNA.

DNA is like everything else: it's not what you have, but how you use it
A new paradigm for reading out genetic information in DNA is described by Dr.

A new spin on DNA
For decades, researchers have chased ways to study biological machines.

From face to DNA: New method aims to improve match between DNA sample and face database
Predicting what someone's face looks like based on a DNA sample remains a hard nut to crack for science.

Read More: DNA News and DNA Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to