Surprisingly, embryos display a high degree of flexibility in correcting disturbances in this process. The study, now published in Cell, shows that no single master regulator controls this nuclear organization. Instead, several redundant mechanisms ensure a robust and adaptable nuclear architecture and enable embryos to correct errors in the initial organization of their nucleus.

Early DNA organization is robust and flexible
When egg and sperm fuse, a comprehensive reorganization of DNA in the nucleus begins. Epigenetics, which regulates gene activity through chemical modifications to DNA and its associated proteins, plays a central role in this process. We wanted to understand how these epigenetic programs influence gene activity and ensure that the cell correctly performs its developmental tasks, explains study leader Prof. Maria-Elena Torres-Padilla, Director of the Institute of Epigenetics and Stem Cells at Helmholtz Munich and Professor in the Faculty of Biology at Ludwig Maximilian University (LMU). Until now, it was unknown whether a single central mechanism controls nuclear organization after fertilization. Our results show that several parallel regulatory pathways are responsible for this, which reinforce each other.

The classic model of the core organization is being questioned
To decipher the mechanisms of this reorganization, the researchers conducted a so-called perturbation screen. They specifically altered epigenetic factors in early mouse embryos to analyze their influence on nuclear organization. The researchers used state-of-the-art molecular biology techniques to map the epigenetic changes (see info box below). The analyses revealed several redundant regulatory mechanisms involved in nuclear organization.

Furthermore, the experiments revealed that—contrary to previous assumptions—gene activity is not strictly determined by spatial position in the nucleus. The position of genes within the nucleus did not always correlate with their activity, says Mrinmoy Pal, lead author of the publication and a doctoral student at the Institute of Epigenetics and Stem Cells. Some genes remained active despite moving to a region of the nucleus traditionally considered inactive, while in other cases a similar relocation led to a drastic reduction in gene expression. This challenges the classic model of nuclear organization and genome function.

Embryos can self-correct errors in early nuclear organization
Even more surprising was the finding that early embryos can self-correct disturbances in nuclear organization. If nuclear organization was disrupted before the first cell division, it could be restored during the second cell cycle. This suggests that early embryos are not only resilient but also possess mechanisms to compensate for errors in their initial nuclear organization.

The researchers discovered that this process is regulated by epigenetic marks inherited from the maternal egg cell. However, if these maternal signals are disrupted, the embryo can activate alternative epigenetic programs to restore the correct nuclear organization—even if these programs may not have originated from the mother. This demonstrates that embryos can utilize different starting points for their development to prevent abnormalities.

Relevance for aging and disease
The study results could have far-reaching implications: In diseases such as progeria, a genetic disorder that leads to premature aging, significant disruptions occur in the DNA associated with the nuclear lamina. Furthermore, various types of cancer are associated with alterations in the spatial organization of the genome. Our findings could help us better understand these mechanisms and, in the long term, develop new approaches to specifically influence epigenetic programs and improve disease progression.

Source: https://www.helmholtz-munich.de/newsroom/news/artikel/wie-sich-die-dna-im-fruehen-embryo-selbst-organisiert