Multi-omics dissection of 3D chromosome structure perturbations in patient-derived cells: lessons from imprinting disorders - CBI Toulouse - Salle De Conférence Nicole Le Douarin (4R4)

The ~ 100 imprinted genes in mammalian genomes are mono-allelically expressed based on their parental origin (i.e. they are only active on the chromosome inherited from the mother or father). Many of these genes cluster together in 20 imprinted domains where dedicated regulatory elements, the so-called “Imprinting Control Regions” (ICRs), dictate allele-specific transcriptional activity throughout the domain. The ICRs at all domains are distinguished by allele-specific DNA methylation, but how they transmit their regulatory instructions over distance differs from one domain to the other. At a subset of imprinted domains, this regulation involves DNA methylation-dependent binding of the CTCF insulator protein to the ICR. We previously showed in mouse cells that CTCF binding at ICRs creates differential 3D chromatin structure, whereby the formation of allele-specific TADs (Topologically Associating Domains) permit rewiring of enhancer-promoter contacts.
While the study of imprinted domains has provided invaluable insights about epigenetics, chromosome structure and gene regulation, their importance expands to human disease as well: imprinting disorders (IDs) are moderately rare developmental disorders that touch ~ 1 in 5000 newborns. IDs are caused by the abnormal activity of specific imprinted genes, resulting in either the complete loss or bi-allelic activity of imprinted genes. While perturbations in 3D chromosome structure are expected for certain IDs, technical limitations have prevented their direct observations. Such information will be highly valuable, as current diagnostics (incorporating structural variation and DNA methylation changes) frequently fails to explain the underlying molecular causes of IDs.
I will present recent collaborative work where we used multi-omics to characterize perturbations in DNA methylation, CTCF binding and TAD structure in cells derived from Silver-Russell ID patients. These studies confirm that valuable diagnostics insights about allele-specific 3D chromosome structure can be obtained from small samples of patient-derived cells, thereby explaining the mechanisms responsible for abnormal activity of imprinted genes.