Cell diversity in the embryo
Epigenetic factors control the development of an organism

Date:
August 4, 2020
Source:
Max-Planck-Gesellschaft
Summary:
Epigenetic factors control the development of an organism.



FULL STORY ==========================================================================
A research team at the Max Planck Institute for Molecular Genetics
in Berlin has explored the role of factors in embryonic development
that do not alter the sequence of DNA, but only epigenetically modify
its "packaging." In the scientific journal Nature, they describe how
regulatory mechanisms contribute to the formation of different tissues
and organs in early mouse embryos.


==========================================================================
A fertilized egg cell develops into a complete organism with a multitude
of different tissues and organs, although the genetic information
is exactly the same in every cell. A complex clockwork of molecules
regulates which cell in the body fulfills each task and determines the
proper time and place to activate each gene.

Epigenetic regulator factors are part of this molecular mechanism and
act to modify the "packaging" of the DNA molecule without altering the underlying genetic information. Specifically, they act to bookmark the
DNA and control what parts can be accessed in each cell.

Most of these regulators are essential, and embryos lacking them tend to
die during the time of development when organs begin to emerge. However,
these regulators may have specific functions that differ in every cell,
making them difficult to study. This has also been a major hindrance for studying these proteins, which are not only relevant for the development
of embryos, but also involved in the formation of cancer.

Detailed examination of embryos "The same regulator is present in all
cells, but can have very different tasks, depending on cell type and time
of development," says Stefanie Grosswendt, one of the first authors of
a new study in the scientific journal Nature.



========================================================================== Grosswendt and her colleague Helene Kretzmer from Alexander Meissner's
lab at the Max Planck Institute for Molecular Genetics (MPIMG) in
Berlin together with Zachary Smith from Harvard University, MA, have
now succeeded in elucidating the significance of epigenetic regulators
for embryonic development with unprecedented precision.

The researchers analyzed ten of the most important epigenetic
regulators. Using the CRISPR-Cas9 system, they first specifically removed
the genes coding for the regulatory factors in fertilized oocytes and
then observed the effects on embryo development days later.

After the embryos had developed for about six to nine days, the team
examined the anatomical and molecular changes that resulted from the
absence of the respective regulator. They found that the cellular
composition of many of the embryos was substantially altered. Cells
of certain types existed in excessive numbers, while others were not
produced at all.

Analyzing thousands of individual cells In order to make sense of these
changes on a molecular level, researchers examined hundreds to thousands
of individual cells from embryos, from which single epigenetic regulators
had been systematically removed. They sequenced the RNA molecules of
almost 280,000 individual cells to investigate the consequences of the
loss of function. RNA relays information encoded on the DNA, allowing researchers to understand the identity and behavior of cells using
sequencing technologies.



==========================================================================
In their analysis, the scientists focused on a phase of development,
in which epigenetic regulators are particularly important. When they
compared the data of altered and unaltered embryos, they identified
genes that were dysregulated, and cell types that are abnormally over-
or underproduced. From this overall picture, they deduced previously
unknown functions of many epigenetic regulators.

Complex effects during development An eight-day-old mouse embryo looks
a bit like a seahorse and does not have any organs yet. "From the outer appearance of an early embryo, one can often only guess which structures
and organs will form and which will not," say bioinformatician Helene
Kretzmer and biologist Zachary Smith, who are also both first authors
of the publication. "Our sequencing allows for a much more precise and
high resolution view." The single-cell analysis gave them a highly
detailed view over the first nine days of mouse development. Often,
switching off a single regulator led to ripple effects throughout the
network of interacting genes, with many differentially activated or
inactivated genes over the course of development.

Removing the epigenetic regulator Polycomb (PRC2) had a particularly
striking impact. "Without PRC2, the embryo looks egg-shaped and
very small after eight and a half days, which is very unusual," says
Kretzmer. "We see vast changes to how DNA is packaged that happens much earlier, long before the embryo develops morphological abnormalities."
The researchers found that PRC2 is responsible for limiting the amount of germline progenitor cells -- the cells that later become sperm and eggs.

Without PRC2, the embryo develops an excessive number of these cells,
loses its shape, and dies after a short time.

Starting point for further analyses "With the combination of new
technologies we addressed issues that have been up in the air for 25
years," says Alexander Meissner, who headed the study. "We now understand better how epigenetic regulators arrange for the many different types
of cells in the body." The work is only the first step for even more
detailed investigations, says Meissner. "Our method lets us investigate
other factors such as transcription or growth factors or even a
combination of these. We are now able to observe very early developmental stages in a level of detail that was previously unthinkable."

========================================================================== Story Source: Materials provided by Max-Planck-Gesellschaft. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Stefanie Grosswendt, Helene Kretzmer, Zachary D. Smith, Abhishek
Sampath
Kumar, Sara Hetzel, Lars Wittler, Sven Klages, Bernd Timmermann,
Shankar Mukherji, Alexander Meissner. Epigenetic regulator
function through mouse gastrulation. Nature, 2020; DOI:
10.1038/s41586-020-2552-x ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/08/200804111532.htm

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