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 scientific journal Nature, They explain how the initial mechanism contributes to the formation of various tissues and organs in the mouse cell.
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 clock of molecules regulates which cell in the body performs each function 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. In particular, they act to bookmark DNA and control which parts can be accessed in each cell.
Most of these regulators are essential, and embryos die due to lack of development when organs begin to emerge. However, these regulators may have specific functions that differ in every cell, making them difficult to study. It has also been a major obstacle to the study of these proteins, which are not only relevant to fetal development, but are also involved in the formation of cancer.
Detailed fetal examination
“The same regulator is present in all cells, but can have very different functions, which depend on cell type and development time,” says Stephanie Grosswend, one of the first authors of a new study in the scientific journal . Nature.
From Alexander Meissner’s lab at the Max Planck Institute for Molecular Genetics (MPIMG) with Zachary Smith from Harvard University, MA in Berlin, Grossswandt and his colleague Helen Kreitzmer now succeed in clarifying the importance of epigenetic regulators for embryonic development with unprecedented accuracy Have been.
The researchers analyzed ten of the most important epigenetic regulators. Using the CRISPR-Cas9 system, they first specifically removed gene coding for regulatory factors in fertilized oocytes and then observed the effects of embryonic development days later.
After the embryos developed for approximately six to nine days, the team investigated the physiological and molecular changes that resulted from the absence of the corresponding regulator. They found that the cellular structure of many embryos was significantly altered. Some cell types were present in large numbers, while others were not produced at all.
Analysis of thousands of individual cells
To make sense of these changes at the molecular level, researchers examined hundreds to thousands of individual cells from the embryo, from which single epigenetic regulators were systematically removed. They sequenced RNA molecules from approximately 280,000 individual cells to examine the consequences of loss of function. RNA relays encoded information on DNA, enabling researchers to understand the identity and behavior of cells using sequencing technologies.
In their analysis, scientists focused on a stage of development, in which epigenetic regulators are particularly important. When they compared data from transformed and unvaccinated embryos, they identified genes that were diseased, and cell types that were abnormally over- or underdeveloped. From this composite diagram, they deduced previously unknown functions of several epigenetic regulators.
Complex effects during development
The eight-day-old rat fetus resembles Sehore and has no organs yet. “From the outer appearance of the early embryo, one can often only guess which structures and organs will form and which will not,” says biologist Helen Kreutzmer and biologist Zachary Smith, who is also the first author of the publication. “Our indexing allows for a much more accurate and higher resolution view.”
Single-cell analysis gave him a detailed description of the first nine days of mouse development. Often, with multiple differentially active genes or inactive genes during development, shutting down a single regulator has an effect on the entire network of gene interactions.
The removal of the epigenetic regulator Polycomb (PRC2) had a particularly striking effect. “Without PRC2, the embryo looks egg-shaped and very small after eight and a half days, which is very unusual,” Kreutzmer says. “We see how DNA is packaged, long before embryonic morphological abnormalities develop.”
Researchers found that PRC2 is responsible for limiting the amount of germline progenitor cells – 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 period of time.
Starting point for further analysis
Alexander Meisner, who led the study, says, “In conjunction with new technologies, we have resolved issues that have arisen in the air for over 25 years.” “Now we better understand how epigenetic regulators arrange many different types of cells in the body.”
Meisner says that this work is the first step for a more detailed investigation. “Our method lets us examine other factors such as transcription or growth factors or even a combination of these. We are now able to follow very early developmental stages to a level of detail that was previously unimaginable.”
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Stephanie Grosswandt et al. Epigenetic regulatory function via mouse gastrulation, Nature (2020). DOI: 10.1038 / s41586-020-2552-x
Provided by the Max Planck Society
Quotes: Epigenetics and cell diversity in embryos (2020, 30 July) retrieved 31 July 2020 from https://phys.org/news/2020-07-epigenetics-cell-diversity-embryo.html.
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