Why do identical cells act differently? Team unravels sources of
cellular 'noise'

Date:
October 14, 2020
Source:
University of Texas at Dallas
Summary:
Researchers have taken an important step toward explaining why
genetically identical cells can produce varying amounts of the same
protein associated with the same gene. Researchers demonstrated that
most of the fluctuations in gene expression between identical cells
occur in the first step of protein production, called transcription.



FULL STORY ========================================================================== University of Texas at Dallas researchers have taken an important step
toward explaining why genetically identical cells can produce varying
amounts of the same protein associated with the same gene.


==========================================================================
In a study published Aug. 18 and appearing in the Sept. 18 print edition
of the journal Nucleic Acids Research, researchers demonstrated that most
of the fluctuations in gene expression between identical cells occur in
the first step of protein production, called transcription.

Understanding why and how such fluctuations, or cellular noise, occur
is a fundamental bioengineering problem, said Dr. Leonidas Bleris,
associate professor of bioengineering in the Erik Jonsson School of
Engineering and Computer Science and Fellow, Cecil H. and Ida Green
Professor in Systems Biology Science.

"The quest to understand cellular noise is driven primarily by our
interest in applying engineering to biology. To paraphrase [physicist]
Richard Feynman, by understanding, we will be able to create," said
Bleris, the corresponding author of the study. "We are interested
in applying control in cells to achieve desirable objectives. The
applications range from sophisticated gene therapy to engineering pathways
in order to produce valuable compounds." Nearly every cell in a person's
body contains the same DNA, the master set of genetic instructions for
making the complex proteins that do most of the biological work. DNA
segments called genes encode specific proteins. But the amount of
protein produced by a given gene -- referred to as gene expression -
- can vary not only between people, but also among identical cells in
the same person. That fluctuation in gene expression between identical
cells is called cellular noise.

Using a combination of experiments and theory, Bleris and his colleagues analyzed each stage of the process by which information in DNA is
converted to proteins, a process referred to as the central dogma of
molecular biology.



==========================================================================
The process begins with transcription of a gene, in which the information
in DNA is copied into a related kind of genetic material called RNA. The
cell then uses the information in the RNA to build proteins.

To understand the source of cellular noise, researchers in the Bleris Lab engineered custom genetic circuits, a synthetic biology approach that
allowed the team to isolate each step of the standard protein-making
process.

Then, the team used the gene-editing tool CRISPR to insert single copies
of these circuits surgically in a predetermined genomic location in
human cells.

This combination of synthetic biology and genome editing made it possible
for the team to analyze fluctuations in cells at different stages of the protein- making process and pinpoint transcription as the source of noise.

The 2020 Nobel Prize in chemistry was awarded Oct. 7 to two scientists who developed the CRISPR/Cas9 genetic scissors -- Dr. Emmanuelle Charpentier, director of the Max Planck Unit for the Science of Pathogens in Berlin,
and Dr.

Jennifer Doudna, a biochemist at the University of California, Berkeley
and a Howard Hughes Medical Institute investigator.

Understanding differences in how genetically identical cells behave can
help scientists develop more effective, targeted therapies, Bleris said.



========================================================================== "Eventually, once we have a better understanding of how our genes
operate in their intrinsically fluctuating environment, we will be able
to engineer a more sophisticated class of gene therapies that can more appropriately address the diseases that ail humanity," said Tyler Quarton PhD'19, one of the study's lead authors.

The research also raises questions for further study.

"Understanding the sources of noise opens the path for asking new
questions: What is the biological function of noise? Is noise used by
cells to introduce diversity, or is it simply a nuisance?" explained
Taek Kang, a biomedical engineering doctoral student, Eugene McDermott
Graduate Fellow and co-lead author.

The team also included Vasileios Papakis BS'20; Khai Nguyen, biomedical engineering senior; Chance Nowak, a molecular and cell biology doctoral student; and Dr. Yi Li, a research scientist in bioengineering.

The research was supported by the National Science Foundation, including Bleris' NSF Faculty Early Career Development (CAREER) Award.


========================================================================== Story Source: Materials provided by
University_of_Texas_at_Dallas. Original written by Kim Horner. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Tyler Quarton, Taek Kang, Vasileios Papakis, Khai Nguyen, Chance
Nowak,
Yi Li, Leonidas Bleris. Uncoupling gene expression noise along the
central dogma using genome engineered human cell lines. Nucleic
Acids Research, 2020; 48 (16): 9406 DOI: 10.1093/nar/gkaa668 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/10/201014161648.htm

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