CTCF mediates allele-specific sub-TAD organization at paternally imprinted gene loci

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Dr Daan Noordermeer (Institut de Biologie Integrative de la Cellule)


Mammalian genes can be mono-allelicly expressed depending on their parental origin, a process called imprinting. Though only a relatively small number of genes are imprinted, this mechanism is of great importance for correct embryonic development. Imprinting is governed by allele-specific DNA methylation at defined Imprinting Control Regions (ICRs), which often influences the binding of the architectural CTCF protein. In collaboration with the group of Robert Feil (IGM-Montpellier, France) we have used a mix of allele-specific ChIP-seq, high-resolution 4C and microscopy to study how 3D chromatin organization is involved at the paternally imprinted Dlk1-Dio3 and Igf2-H19 loci. At both loci, the large majority of 3D interactions are containing within Topologically Associating Domain (TAD). Within these TADs dramatic allele-specific differences can be observed though. The maternal alleles form an invariant and more localized 3D structure that is demarcated by a mix of constitutive and multiple allele-specific CTCF binding sites. As such, these maternal specific sub-TADs encapsulate the ncRNA genes that are active on the maternal allele. In contrast, the paternal alleles adopt a more locus specific 3D organization. The imprinted genes at the Igf2-H19 locus are contained within a sub-TAD with little specific internal structure and dynamics. In contrast, the imprinted protein-coding genes at the Dlk1-Dio3 locus co-occupy a large sub-TAD. Upon activation of these genes, in neuronal cells, interactions globally increase, indicative of a more compacted 3D configuration. In conclusion, our study reveals that paternally imprinted gene loci in mammals are organized into allele-specific sub-TADs. Maternal alleles adopt the most structured and stable 3D organization, despite the imprint being present on the paternal allele. We hypothesize that imprinted gene expression at these loci relies most on the maternal 3D architecture, as supported by previous knock-out studies.

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Dr Daan Noordermeer (Institut de Biologie Integrative de la Cellule)


Dr David LLERES (CNRS UMR5535) Ms Mallory Poncelet (Institute de Biologie Intégrative de la Cellule) Mrs Mélody Matelot (Institute de Biologie Intégrative de la Cellule) Dr Robert Feil (IGMM) Dr Vincent Piras (Institute de Biologie Intégrative de la Cellule)

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