What is a human zygote
The life of every mammal begins with fertilization: two highly specialized cells, the sperm and the egg cell, fuse together to form a common zygote to produce an embryo. The zygote has the potential to produce all cell types in the developing embryo and later in the adult individual. In addition, the cells of the zygote, together with cells of the mother, form the placenta that nourishes the embryo as it grows and develops in the uterus. Because of their “all-inclusive” potential, the zygote and the early embryonic cells, the so-called blastomeres, are called totipotent. As the embryo grows, the cells increasingly specialize, while at the same time their originally unrestricted development potential decreases. In the course of this process, certain cells can then only develop into very specific cell types and organs.
Cell identity and development potential
Which mechanisms determine the identity and the development potential of the cells? All cells carry DNA molecules that contain genes. Genes, in turn, are the code for the blueprints of proteins that fulfill a wide range of structural and regulatory functions in an organism. Interestingly, almost all cells in the body - no matter how different they are - contain an identical set of DNA molecules, the so-called genome. The identity of a cell cannot be determined by irreversible changes in the DNA. Rather, the cell identity is determined by switching different genes on and off in a cell type. This is ensured by special reader molecules such as transcription factors and RNA molecules, which in turn are controlled by regulatory DNA sequences in the genome. This process is called gene expression. It is reflected in a cell type-specific protein production.
Complex of DNA and proteins
Just as people wear different clothes depending on the time of year, personal taste and sporting activity, the DNA within a cell is not naked, but clad with special proteins, so-called histones, and DNA-binding proteins. This complex of DNA and proteins is called chromatin. The DNA is packed into more or less dense chromatin in the cell nucleus. Open and closed arrangements are formed. The way genes and their neighboring sequences are packaged affects the level of gene expression. When the early embryo implants in the uterus in the so-called blastocyst stage, a certain group of cells, the inner cell mass, has formed in it. These cells contain many transcription and chromatin factors that are important for gene expression at this stage and regulate the degree of DNA packaging. The chromatin of these cells is in a relatively open, flexible form and thus enables development (differentiation) into the various cell types of the embryo - but not into the placenta. The cells of the inner cell mass are therefore called pluripotent. In the subsequent differentiation, the key genes that control embryonic gene expression are packaged in inhibitory chromatin structures. These persist in the subsequent cell divisions, so they are "inherited". In addition, cells with different developmental pathways adopt different, specific chromatin structures, which are also retained in further development. Such a type of inheritance of gene expression outside the actual genetic code is called epigenetic memory. It is assumed that the mechanisms of epigenetic memory contribute to the hierarchy of cellular differentiation, on the one hand limiting the differentiation potentials during development and on the other hand preventing the possibility of dedifferentiation.
Reprogrammed developed cells
However, the groundbreaking studies by Sir John Gurdon, a 2012 Nobel Prize in Medicine, have shown that the chromatin landscape of a differentiated cell, called the epigenome, can be reprogrammed - back into an embryo-like state from which even viable offspring can develop can. In this procedure, the nucleus of a fully developed body cell is transferred into a mature, enucleated egg cell, which is known as nucleus transfer or reproductive cloning. Gurdon made his discovery with the cells and eggs of frogs. Later work has shown that eggs and blastomeres can reprogram mature cell nuclei early on in embryos of many species, including mice and cows. It is believed that numerous factors in the egg remove the inhibitory chromatin states from the differentiated nucleus so that important pluripotency genes can be expressed, which then control the development of the embryo. Shinya Yamanaka, the second Nobel Prize in Medicine in 2012, recently demonstrated that the presence of a few transcription factors alone can reprogram fully developed cells directly to pluripotency. So-called induced pluripotent stem cells (iPS) are formed, which are similar to the pluripotent embryonic stem cells (ES) from the inner cell mass of the embryo before implantation in the uterus. Once placed in an early embryo, ES and iPS have the potential to differentiate into all cell types and develop viable offspring. They are also able to produce different mature cells under different in vitro growth conditions. This makes them ideal for modeling diseases and drug tests. Knowledge from basic research in this field can thus contribute to the development of new and safe applications in personalized regenerative medicine.
In the experiments described, however, it became clear that reprogramming using transcription factors is not a very efficient process, which shows how robust the epigenetic memory is and how complex the mechanisms of gene expression are. Likewise, the success rate of reproductive cloning is very low compared to natural reproduction. These observations suggest that the epigenomes of mature egg cells and sperm, in contrast to those of normal body cells, are such that gene expression can easily be switched to totipotency after fertilization. Egg and sperm cells may have certain chromatin structures that normal body cells do not have and are able to pass them on to the embryo unchanged. These very specific chromatin structures, which are a prerequisite for successful embryonic development, presumably arise in the course of a complex epigenetic reprogramming during the development of egg and sperm cells from progenitor cells. Another example of the influence of epigenetic memory are studies on rodents, but also on humans, which show that, for example, diet, smoking habits and pesticide exposure of the parents can lead to physiological changes in the offspring. In many laboratories around the world, research is currently focused on identifying the mechanisms of epigenetic reprogramming in germ cells and early embryos, as well as on epigenetic inheritance between generations. Findings from this research area will, for example, help to identify the background to human infertility in the future. In addition, basic research in the field of inducible reprogramming of body cells will stimulate the development of new forms of therapy in the field of regenerative medicine. Ultimately, this branch of research will one day uncover the secret of recurring totipotency as the basis for new life.
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