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," explains study leader Prof. Maria-Elena Torres-Padilla, Director at the Institute of Epigenetics and Stem Cells at Helmholtz Munich and Professor at the Faculty of Biology at Ludwig-Maximilians-Universität (LMU). "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."
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.
Info box: Study Methods
To investigate the epigenetic mechanisms underlying early nuclear organization, the researchers used a combination of high-resolution molecular techniques:
- Dam-ID: This method identifies DNA regions interacting with the nuclear lamina (a protein scaffold lining the inside of the nuclear envelope, influencing DNA structure) thereby informs about the three-dimensional genome organization.
- RNA-seq: This technique measures gene activity in early embryos to analyze changes in gene expression.
- CUT&RUN and CUT&Tag: These methods enable precise mapping of epigenetic marks that are crucial for regulating nuclear organization.
By combining these techniques, the research team was able to comprehensively map the dynamics of nuclear organization during the first hours of embryonic development and reveal its plasticity.
About Helmholtz Munich
Helmholtz Munich is a leading biomedical research center. Its mission is to develop breakthrough solutions for better health in a rapidly changing world. Interdisciplinary research teams focus on environmentally triggered diseases, especially the therapy and prevention of diabetes, obesity, allergies, and chronic lung diseases. With the power of artificial intelligence and bioengineering, researchers accelerate the translation to patients. Helmholtz Munich has around 2,500 employees and is headquartered in Munich/Neuherberg. It is a member of the Helmholtz Association, with more than 43,000 employees and 18 research centers the largest scientific organization in Germany. More about Helmholtz Munich (Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt GmbH): www.helmholtz-munich.de/en
