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Developmental Heterochromatin Formation Is Accompanied by Changes in Biophysical Properties

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It is commonly known that DNA assembles into heterochromatin, a densely composed structure, thereby preventing access to the information encoded by the DNA and gene expression. Until now it is not completely understood how this structure forms during development, and specifically how the silencing signatures in heterochromatin are acquired. A team of researchers around Prof. Maria-Elena Torres-Padilla, Director of the Helmholtz Munich Stem Cell Center, Director of the Institute for Epigenetics and Stem Cells and Director of Biomedicine of the Pioneer Campus applied high resolution, quantitative imaging and molecular biology approaches to study how heterochromatin forms in early embryos. They were able to demonstrate the importance of phase-separation of pericentromeric heterochromatin in mouse embryonic cells as a reference for mammalian cells and the biophysical changes of heterochromatin during the developmental process. These observations shed light on molecular events at the beginning of life and in addition can also be used in the future as an indication to monitor changes in cellular plasticity.

The hallmark of chromatin silencing in embryos is changing their 3D shape within the nucleus from a ring-shaped structure to spherical domains. How such structure is achieved and maintained is not fully understood. Hints from other species as for instance Drosophila pointed towards studying biophysical properties of these spherical structures, where such structures form membrane-less compartments. This organizational framework is proving to be fundamental for many cellular processes, including in diseased cells, across organisms. In particular, Maria-Elena Torres-Padilla and her team from Helmholtz Munich wondered, whether phase separation of heterochromatin might also be present in mammalian development.

Using a systematic approach, the team of scientists defined five characteristics of liquid-liquid phase separation (LLPS) and methodically probed the emerging structures. The team pushed the technological imaging advances to image chromatin changes in early embryos to relate them to the acquisition of cellular plasticity. After careful examination with the combination of imaging, biophysical and molecular techniques, the researchers, indeed demonstrated events of fusion, increased sphericity and slower molecular exchange within the spherical structures take place in the chromatin of early embryos. Furthermore, when the cells proceed further in their developmental fate and lose cellular plasticity, the biophysical state of heterochromatin undergoes changes as well: it goes from liquid to solid.

This study did not only show the importance of phase-separation of heterochromatin, which was shown for the first time in relation to mammalian development, but also identified how (in mammals) the transition of biophysical properties of pericentromeric heterochromatin parallels with transition in cell developmental state.


About the scientist

Prof. Dr. Maria-Elena Torres-Padilla, Director of the Stem Cell Center (rotating), Director of the Institute for Epigenetics and Stem Cells and Director of Biomedicine of the Pioneer Campus



Original publication

Guthmann et al. (2023): A change in biophysical properties accompanies heterochromatin formation in mouse embryos. Genes & Development. DOI: 10.1101/gad.350353.122