New 3D chromosome structures revealed at the very first stages of embryo development

Published in the journal Nature, this study was conducted in Edith Heard’s laboratory at Institut Curie and at the EMBL in Germany, in collaboration with Peter Fraser’s laboratory at the Babraham Institute in the United Kingdom. It provides new perspectives on the epigenetic roles of the genome structure and destiny of the cell.

For around ten years, we have known that areas along the chromosomes wrap around themselves, forming small piles very close to one another. These pellets - 3D domains known as TAD (Topologically Associated Domains) - play an essential role in gene expression. But what happens at the time of fertilization? Do the chromosomes carry the traces of their parental origin? Researchers from Institut Curie have scrutinized this precise moment using the Single Cell Hi-C technique to collect, analyze and map the genome of over 600 cells from male and female mice embryos.

Unexpectedly, when the embryo is formed from 1, 2 or 4 cells, the preferential contact domains are not distributed randomly but are present on just one of the two chromosome copies, more often the maternal one. These domains contain genes that are kept silent. The copy of the gene on the other parental chromosome, can be expressed:  it is not included in a structural domain, and it corresponds to the paternal allele, if the maternal is included in a structural domain an dvice versa . These first embryonic domains contain a lot of genes that are “subject to temporary imprint”, the expression of which therefore depends on the parental origin. This is the case of the Xist gene, which is responsible for inactivation of the X chromosome in females. The deletion by CRISPR-Cas9 of the majority of the 3D domain upstream of Xist leads to the death of male embryos, underlying the importance of this region in the regulation of expression of the Xist gene.

Later, when the embryo passes the 8-cell stage and pursue its development, the majority of these parental domains disappears and  domains similar to those described for differentiated cells appear (such as TADs).

These results reveal a transient state in which a structure includes the epigenetic heritage of our parents before another 3D structure - specific to the embryo - is introduced. They provide a new perspective on the links between the organization of chromosomes and gene expression. By exploring new candidate genes, they offer new approaches for better understanding the crucial role of the dosing of gene expression at the very early stages of development.

Reference: Parental-to-embryo switch of chromosome organization in early embryogenesis. Samuel Collombet, Noémie Ranisavljevic, Takashi Nagano, Csilla Varnai, Tarak Shisode, Wing Leung, Tristan Piolot, Rafael Galupa, Maud Borensztein, Nicolas Servant, Peter Fraser, Katia Ancelin & Edith Heard. Nature, April 2, 2020. Learn more.