A missing genetic switch at the origin of malformations
Scientists have discovered how the absence of a genetic switch can lead
to malformations during embryonic development.

Date:
December 13, 2021
Source:
Universite' de Gene`ve
Summary:
Embryonic development follows delicate stages: for everything to
go well, many genes must coordinate their activity according to a
very meticulous scheme and tempo. This precision mechanism sometimes
fails, leading to more or less disabling malformations. By studying
the Pitx1 gene, one of the genes involved in the construction of
the lower limbs, a team has discovered how a small disturbance in
the activation process of this gene is at the origin of clubfoot,
a common foot malformation. Indeed, even a fully functional gene
cannot act properly without one of its genetic switches.



FULL STORY ========================================================================== Embryonic development follows delicate stages: for everything to go well,
many genes must coordinate their activity according to a very meticulous
scheme and tempo. This precision mechanism sometimes fails, leading to
more or less disabling malformations. By studying the Pitx1 gene, one of
the genes involved in the construction of the lower limbs, a team from
the University of Geneva (UNIGE), in Switzerland, has discovered how a
small disturbance in the activation process of this gene is at the origin
of clubfoot, a common foot malformation. Indeed, even a fully functional
gene cannot act properly without one of its genetic switches. These short
DNA sequences provide the signal for the transcription of DNA into RNA,
and are essential for this mechanism. And when just one of these switches
is missing, the proportion of cells where the gene is active decreases, preventing the lower limbs from being built properly.

These results, that can be read in the journal Nature Communications,
highlight the hitherto largely underestimated role of genetic switches
in developmental disorders.


========================================================================== During embryonic development, hundreds of genes must be precisely
activated or repressed for organs to build properly. This control of
activity is directed by short DNA sequences that, by binding certain
proteins in the cell nucleus, act as true ON/OFF switches. "When the
switch is turned on, it initiates the transcription of a gene into RNA,
which in turn is translated into a protein that can then perform a
specific task," explains Guillaume Andrey, professor in the Department
of Genetic and Developmental Medicine at the UNIGE Faculty of Medicine,
who led this research. "Without this, genes would be continuously switched
on or off, and therefore unable to act selectively, in the right place
and at the right time." In general, each gene has several switches to
ensure that the mechanism is robust. "However, could the loss of one of
these switches have consequences? This is what we wanted to test here by
taking as a model the Pitx1 gene, whose role in the construction of the
lower limbs is well known," says Raquel Rouco, a post-doctoral researcher
in Guillaume Andrey's laboratory and co-first author of this study.

A decrease in cellular activation that leads to clubfoot To do this, the scientists modified mouse stem cells using the genetic engineering tool CRISPR-CAS 9, which makes it possible to add or remove specific elements
of the genome. "Here, we removed one of Pitx1's switches, called Pen,
and added a fluorescence marker that allows us to visualise the gene activation," explains Olimpia Bompadre, a doctoral student in the research
team and co-first author. "These modified cells are then aggregated with
mouse embryonic cells for us to study their early stages of development." Usually, about 90% of cells in future legs activate the Pitx1 gene, while
10% of cells do not. "However, when we removed the Pen switch, we found
that the proportion of cells that did not activate Pitx1 rose from 10 to
20%, which was enough to modify the construction of the musculoskeletal
system and to induce a clubfoot," explains Guillaume Andrey. Indeed,
the proportion of inactive cells increased particularly in the immature
cells of the lower limbs and in the irregular connective tissue, a tissue
that is essential for building the musculoskeletal system.

The same mechanism in many genes Beyond the Pitx1 gene and clubfoot,
the UNIGE scientists have discovered a general principle whose mechanism
could be found in a large number of genes.

Flawed genetic switches could thus be at the origin of numerous
malformations or developmental diseases. Moreover, a gene does not
control the development of a single organ in the body, but is usually
involved in the construction of a wide range of organs. "A non-lethal malformation, such as clubfoot for example, could be an indicator of
disorders elsewhere in the body that, while not immediately visible,
could be much more dangerous. If we can accurately interpret the action
of each mutation, we could not only read the information in the genome
to find the root cause of a malformation, but also predict effects in
other organs, which would silently develop, in order to intervene as
early as possible," the authors conclude.

========================================================================== Story Source: Materials provided by Universite'_de_Gene`ve. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Raquel Rouco, Olimpia Bompadre, Antonella Rauseo, Olivier Fazio,
Rodrigue
Peraldi, Fabrizio Thorel, Guillaume Andrey. Cell-specific
alterations in Pitx1 regulatory landscape activation caused by
the loss of a single enhancer. Nature Communications, 2021; 12
(1) DOI: 10.1038/s41467-021- 27492-1 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/12/211213084111.htm

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