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 DNA sequence, but only epigenetically modify its “packaging”;. In the scientific journal Nature, describe how regulatory mechanisms contribute to the formation of different tissues and organs in early mouse embryos.
A fertilized egg cell develops in a complete organism with a multitude of different tissues and organs, even if the genetic information is exactly the same in all cells. A complex molecule clock regulates which cell in the body performs each task and determines the appropriate time and place to activate each gene.
Epigenetic regulatory 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 mark DNA and control which parts can be accessed in each cell.
Most of these regulators are essential, and embryos that lack them tend to die during the time of development when organs begin to appear. However, these regulators may have specific functions that differ in each cell, making them difficult to study. This has also been a major obstacle to the study of these proteins, which are not only relevant for embryo development, but are also involved in cancer formation.
Detailed examination of embryos
“The same regulator is present in all cells, but it can have very different tasks, depending on the type of cell and the time of development,” says Stefanie Grosswendt, one of the first authors of a new study in the scientific journal Nature.
Grosswendt and his colleague Helene Kretzmer of Alexander Meissner’s laboratory at the Max Planck Institute for Molecular Genetics (MPIMG) in Berlin together with Zachary Smith of Harvard University, MA, have managed to elucidate the importance of epigenetic regulators for embryonic development. with unprecedented accuracy.
The researchers analyzed ten of the most important epigenetic regulators. Using the CRISPR-Cas9 system, they first specifically removed genes encoding regulatory factors from fertilized oocytes and then observed the effects on embryo development days later.
After developing the embryos for about six or nine days, the team examined the anatomical and molecular changes resulting from the absence of the respective regulator. They found that the cell composition of many of the embryos was substantially altered. There are an excessive number of cells, while others did not occur.
Analysis of thousands of individual cells
To make sense of these changes at the molecular level, the researchers examined hundreds to thousands of individual embryonic cells, from which unique epigenetic regulators had been systematically removed. They sequenced RNA molecules from nearly 280,000 individual cells to investigate the consequences of loss of function. RNA transmits information encoded in DNA, allowing researchers to understand the identity and behavior of cells using sequencing technologies.
In their analysis, scientists focused on a developmental phase, in which epigenetic regulators are particularly important. When comparing altered and unaltered embryo data, they identified genes that were deregulated and cell types that are abnormally overproduced or byproduced. From this overview, they deduced previously unknown functions of many epigenetic regulators.
Complex effects during development
An eight-day-old mouse embryo looks similar to a seahorse and does not yet have organs. “From the external appearance of an early embryo, one can often only guess which structures and organs will form and which will not,” say bioinformatics Helene Kretzmer and biologist Zachary Smith, who are also the first authors of the publication. “Our sequencing allows for a much more accurate, high-resolution view.”
Unicellular analysis provided a very detailed view of the first nine days of mouse development. Often, disabling a single regulator caused ripple effects across the interacting gene network, with many genes activated or inactivated differently throughout development.
The removal of the Polycomb epigenetic regulator (PRC2) had a particularly impactful impact. “Without PRC2, the embryo is egg-shaped and very small after eight and a half days, which is very unusual,” says Kretzmer. “We see immense changes in the way DNA is packaged that happens long before, long before the embryo develops morphological abnormalities.”
The researchers found that PRC2 is responsible for limiting the amount of germline progenitor cells, cells that then 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 analysis
“With the combination of new technologies we addressed issues that have been on the air for 25 years,” says Alexander Meissner, who led the study. “We now better understand how epigenetic regulators arrange for the many different types of cells in the body.”
Meissner states that the work is the first step for even more detailed research. “Our method allows us to investigate other factors such as transcription or growth factors or even a combination of these. We can now observe very early stages of development at a level of detail that was previously unthinkable.”
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Stefanie Grosswendt et al. Epigenetic regulatory function through mouse gastrulation, Nature (2020). DOI: 10.1038 / s41586-020-2552-x
Provided by Max Planck Society
Citation: Epigenetics and cell diversity in the embryo (2020, July 30) retrieved July 31, 2020 at https://phys.org/news/2020-07-epigenetics-cell-diversity-embryo.html
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