Epigenetic flexibility helps embryos avoid developmental errors

An international research team led by Helmholtz Munich has, for the first time, provided a detailed insight into how the spatial organization of genetic material is established in the cell nucleus of early embryos within the first hours after fertilization. Surprisingly, embryos demonstrate a high degree of flexibility in responding to disruptions in this process. The study, now published in Cell, reveals that no single master regulator controls this nuclear organization. Instead, multiple redundant mechanisms ensure a robust and adaptable nuclear architecture, allowing embryos to correct errors in the initial organization of their nucleus.

Early DNA organization is robust and flexible

When the egg and sperm fuse, a comprehensive reorganization of DNA begins within the nucleus. Epigenetics plays a crucial role in this process, regulating gene activity through chemical modifications on DNA and its associated proteins.

We wanted to understand how these epigenetic programs influence gene activity and ensure that the cell correctly executes its developmental tasks. Previously, it was not known whether a single central mechanism controlled nuclear organization after fertilization. Our results show that after fertilization, multiple parallel regulatory pathways control nuclear organization, reinforcing each other.”

Prof. Maria-Elena Torres-Padilla, Study Leader, Director at the Institute of Epigenetics and Stem Cells at Helmholtz Munich and Professor at the Faculty of Biology at Ludwig-Maximilians-Universität (LMU)

Challenging the classical model of nuclear organization

To decipher the mechanisms of this reorganization, the researchers conducted a mid-scale perturbation screening in mouse embryos. To map epigenetic changes in early embryos, they employed state-of-the-art molecular biology techniques (see information box below). The analyses uncovered multiple redundant regulatory mechanisms involved in nuclear organization.

Furthermore, the experiments revealed that – contrary to previous assumptions – gene activity is not strictly determined by nuclear positioning.

“The position of genes within the nucleus did not always correlate with their activity,” explains Mrinmoy Pal, first author of the publication and doctoral researcher at the Institute of Epigenetics and Stem Cells. Some genes remained active despite shifting to a nuclear region traditionally considered inactive, while similar relocations in other cases led to a drastic reduction in gene expression. “This challenges the classical model of nuclear organization and genome function,” Pal concludes.

Embryos can self-correct early nuclear organization errors

Even more surprising was the finding that embryos can self-correct disruptions in nuclear organization, even after the first division of the fertilized egg. If nuclear organization was disrupted prior to the first cell division, it could get 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. If these maternal signals are disrupted, the embryo can activate alternative epigenetic programs to eventually restore correct nuclear organization that might  not originate from the mother. This indicates that embryos can utilize different starting points for their development to prevent developmental defects.

Relevance for aging and disease

The findings from study could have broad implications: in diseases such as Progeria, a genetic disorder causing premature aging, significant disruptions occur in DNA associated with the nuclear lamina. Additionally, several cancers are linked to changes in nuclear genome organization. “Our results could help to better understand these mechanisms and, in the long term, develop new approaches to specifically influence epigenetic programs to improve disease outcomes,” says Torres-Padilla.