DNA discovery reveals a critical 'accordion effect' for switching off
genes
Date:
April 5, 2022
Source:
Walter and Eliza Hall Institute
Summary:
Researchers have revealed how an 'accordion effect' is critical to
switching off genes, in a study that transforms the fundamentals
of what we know about gene silencing. The finding expands our
understanding of how we switch genes on and off to make the
different cell types in our bodies, as we develop in the womb.
FULL STORY ==========================================================================
WEHI researchers have revealed how an 'accordion effect' is critical to switching off genes, in a study that transforms the fundamentals of what
we know about gene silencing.
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The finding expands our understanding of how we switch genes on and off
to make the different cell types in our bodies, as we develop in the womb.
It also offers a new way to potentially harness gene silencing in the
future, to treat or reverse the progression of a broad range of diseases including cancer, congenital and infectious diseases.
Gene silencing is regulated by how tightly DNA is packed into a cell. The findings from a team led by Dr Andrew Keniry and Professor Marnie Blewitt reveal a new accordion-like trigger that is crucial to the process.
The research is published in Nature Communications.
All in the DNA The DNA that makes up our genetic material is wrapped
tightly around proteins, like thread wraps around a spool. When it
is loosely packaged the genes can be switched on; when it is tightly
compacted, genes are switched off.
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In the new study, the researchers found that to switch a gene off, the DNA packaging must initially loosen up, before then being tightly compressed.
Professor Marnie Blewitt said discovering the accordion-style trigger
took the team by surprise, changing their fundamental understanding to
date of this critical process.
"We were amazed to learn that the DNA first needs to relax, to trigger
this process," she said.
"Similar to how an accordion needs to open up before it is compressed
to elicit a musical note, we found our DNA needs to be opened up first,
before it can be compressed and the gene is silenced." Silencing power
Dr Andrew Keniry said gene silencing had amazing therapeutic potential.
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"If we could learn exactly how to switch genes off, we may one day be able
to switch off detrimental genes in a variety of diseases," Dr Keniry said.
"If you could switch off the oncogenes that drive cancer, for example,
you potentially could have a new treatment.
"To be able to realise this dream, we first need to know how the process happens so it can be mimicked with medicines, and our discovery is one
more vital piece of this puzzle." The fundamental mechanistic study
was focused on efficiently searching for new factors involved in the
gene silencing process.
To enable this, the team created a system they called 'Xmas', based on red
and green tags that are normally switched off during development. The
system reported gene activity from each X chromosome through the
expression of a red and green fluorescent protein, to reveal if the gene silencing process was occurring normally.
The study uncovered a new molecular mechanism of gene silencing, with the researchers pinpointing the protein complex required for this process,
known as the BAF complex.
The next steps for the research will investigate why the accordion
effect is required for gene silencing and the relevance of the process
for genes on other chromosomes, such as the autosomes.
This research was supported by the Dyson Bequest, the DHB Foundation, the Australian National Health and Medical Research Council, the Victorian
State Government and a Bellberry-Viertel Senior Medical Research
fellowship. The work also involved collaborations with other Australian researchers at Monash BioMedical Discovery Institute and The University
of Tasmania.
========================================================================== Story Source: Materials provided by Walter_and_Eliza_Hall_Institute. Note: Content may be edited for style and length.
========================================================================== Journal Reference:
1. Andrew Keniry, Natasha Jansz, Linden J. Gearing, Iromi Wanigasuriya,
Joseph Chen, Christian M. Nefzger, Peter F. Hickey, Quentin
Gouil, Joy Liu, Kelsey A. Breslin, Megan Iminitoff, Tamara Beck,
Andres Tapia del Fierro, Lachlan Whitehead, Andrew Jarratt, Sarah
A. Kinkel, Phillippa C.
Taberlay, Tracy Willson, Miha Pakusch, Matthew E. Ritchie,
Douglas J.
Hilton, Jose M. Polo, Marnie E. Blewitt. BAF complex-mediated
chromatin relaxation is required for establishment of X chromosome
inactivation.
Nature Communications, 2022; 13 (1) DOI: 10.1038/s41467-022-29333-1 ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2022/04/220405084554.htm
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