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Developmental biology

Fitting the DNA in the cell nucleus

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.

© Helmholtz Zentrum München Individual embryonic cells are depicted through their cellular membranes (green). The small inner cercle depicts the nuclear lamina, where the genome becomes attached.

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,” says 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.

Further information

Original publication:

Borsos M, Perricone SM et al. (2019): Genome-lamina interactions are established de novo in the early mouse embryo. Nature. DOI: 10.1038/s41586-019-1233-0

* DNA adenine methyltransferase identification (DamID) is a molecular biological technique that permits one to determine the positions at which specific proteins are in proximity to chromosomal DNA.

** Lamina-associated domains (LAD) are segments of chromosomes that are attached to the membrane which surrounds the cell nucleus.

*** The term ‘epigenetic’ refers to various mechanisms that regulate the activity of genes without altering the sequence of bases in the genomic DNA.

As German Research Center for Environmental Health, Helmholtz Zentrum München pursues the goal of developing personalized medical approaches for the prevention and therapy of major common diseases such as diabetes mellitus, allergies and lung diseases. To achieve this, it investigates the interaction of genetics, environmental factors and lifestyle. The Helmholtz Zentrum München has about 2,500 staff members and is headquartered in Neuherberg in the north of Munich. Helmholtz Zentrum München is a member of the Helmholtz Association, a community of 19 scientific-technical and medical-biological research centers with a total of about 37,000 staff members. 

The research of the Institute of Epigenetics and Stem Cells (IES) is focused on the characterization of early events in mammalian embryos. The scientists are especially interested in the totipotency of cells which is lost during development. Moreover, they want to elucidate who this loss is caused by changes in the nucleus. Their main goal is to understand the underlying molecular mechanisms which might lead to the development of new therapeutic approaches.

As one of Europe's leading research universities, LMU Munich is committed to the highest international standards of excellence in research and teaching. Building on its 500-year-tradition of scholarship, LMU covers a broad spectrum of disciplines, ranging from the humanities and cultural studies through law, economics and social studies to medicine and the sciences. 15 percent of LMU‘s 50,000 students come from abroad, originating from 130 countries worldwide. The know-how and creativity of LMU's academics form the foundation of the University's outstanding research record. This is also reflected in LMU‘s designation of as a "university of excellence" in the context of the Excellence Initiative, a nationwide competition to promote top-level university research. 

Research at the Hubrecht Institute is pioneering in developmental and stem cell biology. The institute encompasses 24 research groups that perform fundamental, multidisci-plinary research on healthy and diseased cells, tissues and organisms. The Hubrecht Institute is a research institute of the Royal Netherlands Academy of Arts and Sciences (KNAW), situated on the Utrecht Science Park ‘De Uithof’. Since 2008, the Hubrecht is affiliated with the UMC Utrecht. This allowed the institute to grow into an internationally renowned research institute and facilitated the link with (pre)clinical research. The Hubrecht Institute has a partnership with the European Molecular Biology Laboratory (EMBL) based on shared institutional goals, scientific synergy and complementarity.