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3D genome organization directs the expression of genes implicated in imprinting diseases

Diseases related to parental imprinting defects are characterized by a variety of symptoms including growth alterations, endocrine defects and mental disability. A collaboration between teams from the I2BC and the IGMM (Montpellier) has shown that the three-dimensional (3D) organization of chromosomes controls the expression of genes involved in these complex syndromes. Their work has just been published in the journal Genome Biology.

In mammals, genetic information is carried by two copies of each chromosome, one inherited from the mother and the other from the father. The majority of genes are expressed at similar levels on these two copies, but about 150 genes escape this rule. These genes carry a "signal" on one of the two chromosomal copies that indicates whether it was inherited from the father or mother. This label, which allows them to be distinguished, is called a "parental imprint" and takes the form of an epigenetic modification of the DNA (DNA methylation). This DNA methylation in turn regulates the expression of these genes. As a result, genes subjected to parental imprinting acquire opposite expression patterns and are de facto expressed from only one of the two copies of the chromosome. How this epigenetic imprint regulates the activity of genes remains poorly understood.
Four syndromes related to parental imprinting dysfunction (Beckwith-Wiedemann, Silver-Russell, Kagami-Ogata and Temple syndromes) are caused by genetic or epigenetic anomalies occurring within two large gene clusters. These anomalies lead to the loss of distinction between the chromosomes and lead to various symptoms such as developmental alterations, aberrant growth and endocrine defects. In these two chromosome regions, it is the copy inherited from the father that carries the DNA methylation imprint in healthy individuals.

The team of Daan Noordermeer in collaboration with the team of Robert Feil (Institute of Molecular Genetics of Montpellier) have shown that the murine CTCF factor, a protein that is essential for the folding of chromosomes, binds at more sites on the two regions inherited by the mother (where the methylation imprint is absent).

By combining high-resolution genomics and microscopy approaches, they have shown that these additional CTCF binding sites lead to the formation of new "Topological Association Domains" or TADs on the maternal chromosome. TADs are structural and functional units of genomes that restrict interactions between genes and regulatory elements, thus contributing to the expression of genes present within the TAD.

A. The genomic region containing the genes responsible for Kagami-Ogata and Temple syndromes is separated into three structural domains (“TADs”) on the chromosome inherited from the mother, but only two domains are present on the chromosome inherited from the father. On this latter chromosome, an epigenetic “signal” prevents a third instance of binding by the CTCF protein. B. High-resolution microscopy of a separated red and green gene on the chromosome from the mother and their overlap (yellow) on the chromosome from the father. C. High-resolution genomics approaches identify three TADs on the chromosome from the mother and confirms the fusion of two TADs on the chromosome from the father.

The two teams show that the CTCF binding sites, in the two regions subject to parental imprinting, lead to a different subdivision of TADs on the maternal and paternal chromosome. This difference in structural organization controls the expression of the genes in the region and leads to their expression from only one of the two copies, either the maternal chromosome or the paternal chromosome.

These results obtained in mouse cells further improve our current understanding of the deregulations occurring in syndromes related to parental imprint abnormalities. Moreover, in the future, these results may help to improve patient diagnosis.

CTCF modulates allele-specific sub-TAD organisation and imprinted gene activity at the mouse Dlk1-Dio3 and Igf2-H19 domains.
David Llères, Benoît Moindrot, Rakesh Pathak, Vincent Piras, Mélody Matelot, Benoît Pignard, Alice Marchand, Mallory Poncelet, Aurélien Perrin, Virgile Tellier, Robert Feil* and Daan Noordermeer*.
Genome Biology, 2019. DOI : 10.1186/s13059-019-1896-8

Contact : Daan Noordermeer

by Communication - published on