The architecture of the DNA-protein complexes that make up the genome in each cell nucleus regulates the course of early embryonic development. Researchers at the Helmholtz Zentrum München and the LMU in collaboration with the Hubrecht Institute, have now shown that this architecture is not inherited, but must be assembled new - in a process that is regulated largely by epigenetic mechanisms. The new study appears in the journal Nature.
Mammalian embryogenesis begins with fertilization, the entry of a sperm cell into an egg cell. These two cells, each of which contains a single ("haploid") set of chromosomes, fuse to form the zygote or one-cell embryo, which therefore has a double or "diploid" chromosome complement. The zygote then divides, successively giving rise to the 2-, 4-, 8- and 16-cell embryo. During this period, the molecular organization of the chromosomes undergoes a series of changes. How these changes are accomplished is not well understood, but recent findings have begun to shed light on the process.
The spatial organization of the genome is not inherited
In collaboration with Jop Kind at the Hubrecht Institute in Utrecht, we have applied the DamID technique to mammalian embryos for the first time."
Prof. Dr. Maria Elena Torres-Padilla, who co-directed the study
Torres-Padilla is Director of the Institute for Epigenetics and Stem Cell Research (IES) at the Helmholtz Zentrum München and Professor of Stem Cell Biology at LMU Munich. The DamID procedure results in the formation of covalent links between nearby DNA sequences and the proteins that make up the nuclear lamina, a fibrous meshwork on the inner surface of the nuclear membrane. By determining the nucleotide sequences of the lamina-associated DNA segments, the researchers are able to determine the three-dimensional configuration of the genomic DNA within the cell nucleus.
Torres-Padilla was surprised by the results. We found that the spatial organization of the genome is not inherited, but is first established in the embryo." At the beginning of embryonic development, i.e. after the fusion of the germ cells, the maternal and paternal genomes interact with the proteins of the nuclear lamina to form what are called lamina-associated domains (LADs). However, these complexes are not detectable in the egg. Clearly, this particular spatial configuration of the genome is set up very quickly during the first period of early embryogenesis.
Epigenetic alteration of chromosomal configurations
In addition, the authors showed that this whole process is regulated by epigenetic mechanisms. For example, the presence of a single gene, called Kdm5b, specifically inhibited the interaction of the paternal DNA with the nuclear lamina. "Thanks to our new approach, we are now in a position to investigate cells in early mammalian embryos more thoroughly," says Torres-Padilla. She hopes that such studies will lead to a deeper understanding of epigenetic mechanisms, which are also of crucial significance for human development and health. For example, the incidence of many chronic disorders, such as Type-2 diabetes, Alzheimer's disease and cancer, cannot be explained by a combination of genetic and environmental factors alone. Epigenetic mechanisms are also likely to play a role in their pathogenesis.
Helmholtz Zentrum Muenchen - German Research Centre for Environmental Health
Perricone, S.M. et al. (2019) Genome-lamina interactions are established de novo in the early mouse embryo. Nature. doi.org/10.1038/s41586-019-1233-0.