image: Left: Visualization of the formation of LADs in embryos at different stages of development. The arrow indicates a region of the genome contacting the nuclear lamina in the paternal pronucleus. Similarly, these regions are visible in the maternal pronucleus and in the other developmental stages. Right: Identification of genomic regions that contact the nuclear lamina (peaks in the profile) in the same cells as shown by microcopy (left). The black bars on top of the profiles depict genomic regions that are located at the nuclear lamina at the different stages of development. Note that, similar to what is observed by microscopy, LADs are already established in zygotes (purple profiles). view more
Credit: Sara Perricone and Máté Borsos, copyright Hubrecht Institute and Helmholtz Center Munich
The fundamental organization of the DNA in active and inactive compartments arises immediately after fertilization of the oocyte, even before genes are activated. This was discovered by researchers from the Hubrecht Institute and the Helmholtz Center Munich and will lead to a better understanding of the mechanisms behind the development of a single fertilized oocyte into a complete organism that consists of many different cell types. The results were published in the scientific journal Nature on the 22nd of May.
From fertilized oocyte to complete organism
A fertilized oocyte, a zygote, eventually develops into a whole organism that consists of trillions of cells with a wide diversity of functions. Despite these various functions, the DNA in all of these cells is the same. The identity of cells is determined by sets of genes that are turned 'on' and 'off'. But how do all of these cells organize which genes are turned 'on' and 'off'?
DNA organization in the nucleus
The DNA is not just haphazardly deposited into the nucleus of the cell, but instead spatially organized in active and inactive compartments. The compartments that are not active are tethered to the edge of the round shaped nucleus. This edge consists of a thin layer that is called the lamina, and these DNA compartments are therefore called Lamina Associated Domains, or LADs. "You can compare the DNA that is divided into LADs and inter-LADs to a very long garland, that is not tangled up on the floor of the living room, but instead attached to the ceiling at anchor points," says Jop Kind, group leader at the Hubrecht Institute. "This results in a spatially organized chromosome-partitioning that makes the untethered parts (the inter-LADs) more accessible for activation compared to the parts that are tethered to the ceiling (the LADs)." In cells with different functions, different parts of the DNA are tethered to the lamina, although there are certain LADs that are present in all cell types.
New method
Different cell types thus differ in the sets of genes that are turned 'on' and 'off' and which parts of the DNA are tethered to the lamina. Until now it was unclear which of these characteristics occurs first in the cell. The researchers therefore developed a new method through which they could analyze the organization of the DNA in LADs and inter-LADs very early in the development of an embryo. They did this at different timepoints, from the early zygote, even before genes are activated in the embryo, until the moment at which the embryo consists of eight cells.
Which characteristic forms first?
The researchers discovered that the DNA in the zygote is already organized in LADs and inter-LADs before genes are activated in the embryo. LADs are therefore formed before the activity of genes starts to play a role. In addition, the researchers found that the activity of genes during the development of an embryo changes in accordance with changes in the LAD structure. Therefore, it seems that organizing the DNA into LADs and inter-LADs is a very early event in a process that eventually leads to the identity of a cell.
Primitive LADs
The LADs that were found in the early zygote turned out to very closely match the LADs that are present in all cell types. In addition, these LADs match the LADs in the so-called "pluripotent stem cells", stem cells that can still develop into all cell types of the embryo. "The LADs in the zygote therefore seem to be 'primitive' LADs," says Kind, "some sort of basic suspension system in the cell nucleus that can be built upon when the cell specializes."
Future
The newly developed method and its first results show that this approach can be used to further investigate the mechanisms involved in the formation of an entire organism from a single fertilized oocyte. In the future this will lead to a better understanding of normal development, but will also give more insights in what can go wrong during the development of an embryo.
###
Publication
Genome-lamina interactions are established de novo in the early mouse embryo. Máté Borsos*, Sara M. Perricone*, Tamás Schauer, Julien Pontabry, Kim L. de Luca, Sandra S. de Vries, Elias R. Ruiz-Morales, Maria-Elena Torres-Padilla**en Jop Kind**. Nature, 2019.
*equal contribution, **co-senior authors
Jop Kind is group leader at the Hubrecht Institute and Oncode Investigator.
Maria-Elena Torres-Padilla is group leader and director of the Institute of Epigenetics and Stem Cells (IES), Helmholtz Center Munich and professor of Stem cell biology at the Ludwig-Maximilians University.
About the Hubrecht Institute
The Hubrecht Institute is a research institute focused on developmental and stem cell biology. It encompasses 24 research groups that perform fundamental and multidisciplinary research, both in healthy systems and disease models. The Hubrecht Institute is a research institute of the Royal Netherlands Academy of Arts and Sciences (KNAW), situated on the Utrecht Science Park. Since 2008, the institute is affiliated with the UMC Utrecht, advancing the translation of research to the clinic. The Hubrecht Institute has a partnership with the European Molecular Biology Laboratory (EMBL). For more information, visit http://www.hubrecht.eu.
About the Helmholtz Zentrum München
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 and lung diseases. To achieve this, it investigates the interaction of genetics, environmental factors and lifestyle. The Helmholtz Zentrum München has about 2,300 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 18 scientific-technical and medical-biological research centers with a total of about 37,000 staff members. www.helmholtz-muenchen.de
Note for the press
For more information, please contact Melanie Fremery, the communications officer of the Hubrecht Institute: m.fremery@hubrecht.eu or 0031658911260 (between during 9:00AM and 6:00PM Dutch time). Between the 24th and the 30th of May she will be unavailable, during this period you can contact Jop Kind: j.kind@hubrecht.eu and 0031302121800.
Journal
Nature