Gene expression in the nervous system: Mechanism for its targeted
stimulation discovered
Date:
May 4, 2022
Source:
Universita"t Bayreuth
Summary:
Genes are the carriers of our genetic information. They are read
in our cells and used to produce ribonucleic acids (RNAs). During
this process, termed transcription, the enzyme RNA polymerase
II has a decisive influence on the exact time at which genes are
read and on the intensity with which this happens. In their recent
article, researchers have shown exactly how RNA polymerase II is
activated in nerve cells, and how this stimulates gene expression,
the targeted use of genetic information.
Their discoveries contain valuable starting points for further
biomedical research.
FULL STORY ========================================================================== Genes are the carriers of our genetic information. They are read in
our cells and used to produce ribonucleic acids (RNAs). During this
process, termed transcription, the enzyme RNA polymerase II has a decisive influence on the exact time at which genes are read and on the intensity
with which this happens. In their recent Nature Communications article, researchers from the University of Bayreuth have shown exactly how RNA polymerase II is activated in nerve cells, and how this stimulates gene expression, the targeted use of genetic information. Their discoveries
contain valuable starting points for further biomedical research.
==========================================================================
The new research results were obtained in close cooperation between the Bayreuth research team led by Dr. Claus-D. Kuhn and partner universities
in South Korea and Switzerland. In the jointly discovered mechanism
the team found enhancer RNAs (eRNAs) to play a key role in activating
RNA polymerase II -- Pol II for short. Enhancer RNAs are non-coding,
i.e. they are RNA molecules that are not used as blueprints for protein production. As the researchers were able to decipher, enhancer RNAs
switch on the activity of Pol II. They do so by detaching NELF (Negative Elongation Factor), a large molecular complex bound to Pol II, from Pol
II. NELF normally blocks Pol II activity by binding to it.
However, enhancer RNAs can only act as "liberators" of Pol II under two conditions: They need to have a minimum length and they need to be of a characteristic molecular composition. If both these conditions are met, multivalent interactions occur between the long enhancer RNAs and the
NELF complex, as the Bayreuth researchers discovered. This means that
enhancer RNAs simultaneously dock to a number of different binding sites
that are distributed over several subunits of NELF. Only by means of
these interactions are they able to detach NELF from Pol II. Enhancer
RNAs thereby ensure that Pol II is reactivated and resumes the process
of transcription following the NELF-induced paused state. "For the first
time, we have succeeded in demonstrating a direct mechanistic connection between enhancer RNAs and the transcription process controlled by Pol II,
which is a key component of gene expression," says Dr.
Claus-D. Kuhn, Heisenberg Professor for RNA Biochemistry at the University
of Bayreuth.
The Bayreuth researchers and their cooperation partners gained their
new insights by studying cortical neurons in mice. As soon as these
neurons are stimulated by electrical stimuli, they produce large
amounts of enhancer RNAs for a short period of time. These non-coding
RNAs then activate genes that are important for nerve growth and
their improved interconnectivity. They achieve this by detaching
the NELF complex from Pol II. "To the best of our knowledge, this
is the first time that a direct, mechanistic link between neuronal
activity, enhancer transcription, and gene activation has been shown,"
says Bayreuth biochemist Dr. Vladyslava Gorbovytska, first author of
the study. "In the future, the knowledge we have gained could make
it possible to specifically modulate brain activity. This would be a significant asset for the treatment of many neurodegenerative diseases."
The study, published in Nature Communications, also expands previous
knowledge regarding the role of enhancers, which are regulatory areas in
DNA. Enhancers are known to be indispensable for initiating transcription
in higher organisms, such as humans. This is the case as they serve
as binding platforms for so- called transcription factors. The research conducted at the University of Bayreuth now shows that they influence gene expression in yet another, universally applicable way: Enhancers are read
by Pol II, resulting in large amounts of enhancer RNAs. In this respect,
these non-coding RNAs owe their existence precisely to the enzyme that
they later release from a paused state and activate.
========================================================================== Story Source: Materials provided by Universita"t_Bayreuth. Note: Content
may be edited for style and length.
========================================================================== Journal Reference:
1. Vladyslava Gorbovytska, Seung-Kyoon Kim, Filiz Kuybu, Michael
Go"tze,
Dahun Um, Keunsoo Kang, Andreas Pittroff, Theresia Brennecke,
Lisa-Marie Schneider, Alexander Leitner, Tae-Kyung Kim,
Claus-D. Kuhn. Enhancer RNAs stimulate Pol II pause release by
harnessing multivalent interactions to NELF. Nature Communications,
2022; 13 (1) DOI: 10.1038/s41467-022-29934-w ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2022/05/220504110427.htm
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