CTCF controls imprinted gene activity at the mouse<i>Dlk1-Dio3</i>and<i>Igf2-H19</i>domains by modulating allele-specific sub-TAD structure

Llères, David; Moindrot, Benoît; Pathak, Rakesh; Piras, Vincent; Matelot, Mélody; Pignard, Benoit; Marchand, Alice; Poncelet, Mallory; Perrin, Aurélien; Tellier, Virgile; Feil, Robert; Noordermeer, Daan

doi:10.1101/633065

Cited by 3 publications

(8 citation statements)

References 53 publications

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“…Previous work described differential binding of CTCF at the H19/Igf2 locus, specifically at the ICR next to H19 (Llères et al, 2019). It is possible that the differential binding of CTCF can alter the chromatin contacts of the ICR not only locally (Llères et al, 2019), but might have larger effects on chromosome topology, even to the extent of changing TAD structures at the locus. CTCF has been shown to be important for the manifestation of TAD borders at a number of disease-associated gene loci (Hnisz et al, 2016;Ji et al, 2016).…”

Section: Chromatin Contacts At the Imprinted H19/igf2 Locusmentioning

confidence: 99%

“…For instance, several studies in human cells suggest allele-specific CTCF-mediated loops at the imprinted genes H19 and IGF2 (Dixon et al, 2015;Rao et al, 2014;Tan et al, 2018b). In mice, a recent study finds allele-specific contacts using 4C at the murine H19/Igf2 locus in ESCs, accompanied by allele-specific DNA methylation and CTCF binding at the imprinting control region (ICR) immediately upstream of H19 (Llères et al, 2019). Other loci have been described to display allele-specific contacts, such as the immunoglobulin heavy chain locus (Holwerda et al, 2013) and other imprinted loci, such as the Dlk1-Dio3 locus (Llères et al, 2019).…”

Section: The Abundance Of Allele-specific Chromatin Contacts In the Gmentioning

confidence: 99%

“…In mice, a recent study finds allele-specific contacts using 4C at the murine H19/Igf2 locus in ESCs, accompanied by allele-specific DNA methylation and CTCF binding at the imprinting control region (ICR) immediately upstream of H19 (Llères et al, 2019). Other loci have been described to display allele-specific contacts, such as the immunoglobulin heavy chain locus (Holwerda et al, 2013) and other imprinted loci, such as the Dlk1-Dio3 locus (Llères et al, 2019). Reassessment of allele-specific Hi-C data has recently shown a generally higher likelihood for imprinted genes to be found at differential chromatin loops (Greenwald et al, 2019).…”

Section: The Abundance Of Allele-specific Chromatin Contacts In the Gmentioning

confidence: 99%

“…To begin exploring specific chromatin contact differences between alleles, I chose to investigate the topology of the previously described H19/Igf2 locus in F123 mESCs. The imprinted control region immediately next to H19 has been described to form maternalspecific interactions in mESCs with a downstream region called the H19/Igf2 distal anchor domain (HIDAD) within the borders of the H19/Igf2 TAD (Llères et al, 2019;Rao et al, 2014;Tan et al, 2018b). This interaction leads to maternal-specific expression of H19 (Llères et al, 2019).…”

Section: Chromatin Contacts At the Imprinted H19/igf2 Locusmentioning

confidence: 99%

“…The imprinted control region immediately next to H19 has been described to form maternalspecific interactions in mESCs with a downstream region called the H19/Igf2 distal anchor domain (HIDAD) within the borders of the H19/Igf2 TAD (Llères et al, 2019;Rao et al, 2014;Tan et al, 2018b). This interaction leads to maternal-specific expression of H19 (Llères et al, 2019). On the paternal allele, HIDAD interacts with the promoter of Igf2 which leads to paternal-specific expression of Igf2.…”

Section: Chromatin Contacts At the Imprinted H19/igf2 Locusmentioning

confidence: 99%

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Methods for mapping 3D chromosome architecture

2019

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Several people have supported and helped me to during my PhD with guidance and advice, with contributions to the here presented work, but also with their friendship. First, I would like to thank my supervisor Ana for guiding me though my PhD and helping me manage three interesting but also challenging projects with ups and downs along the way. Thank you for lots of great advice and for helping me stay positive in difficult times.Many thanks to Uwe and Robert for our annual committee meetings, your time and advice, and my PhD committee for taking the time to review this thesis.I would like to thank Sasha (Alexander) for working with me on what sometimes seemed to be endless GAM optimisations, and for advice in all possible and impossible challenges that the wet lab provides. Many thanks go to all bioinformaticians that worked with me during my PhD; Ibai, Sasha (again), Ehsan, Christoph, Dominik, Tom, Rob, Mariano, and Markus. All of you are indispensable to making these projects a success, and you did not only do an amazing job but also managed to teach me a basic understanding of data analysis. Many thanks to Rob for all his prior work on GAM and for teaching me GAM when I joined the lab. Thank you, Enric, for joining our lab for the task of setting up an in-house WGA, your initiative and your work made this possible. Special thanks go to Gesa for helping me out when collecting nuclear profiles got too much for just one person, and for being a great friend. Without you the lab would have been only half the fun. I would also like to thank Izabela for her contribution to our final optimisations, which gave me a lot of positive energy when I really needed it, and everyone else in the Pombo lab for their help and/or friendship;

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Section: Chromatin Contacts At the Imprinted H19/igf2 Locusmentioning

confidence: 99%

Section: The Abundance Of Allele-specific Chromatin Contacts In the Gmentioning

confidence: 99%

Section: The Abundance Of Allele-specific Chromatin Contacts In the Gmentioning

confidence: 99%

Section: Chromatin Contacts At the Imprinted H19/igf2 Locusmentioning

confidence: 99%

Section: Chromatin Contacts At the Imprinted H19/igf2 Locusmentioning

confidence: 99%

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Methods for mapping 3D chromosome architecture

2019

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CTCF modulates allele-specific sub-TAD organization and imprinted gene activity at the mouse Dlk1-Dio3 and Igf2-H19 domains

Llères¹,

Moindrot²,

Pathak³

et al. 2019

Genome Biol

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BackgroundGenomic imprinting is essential for mammalian development and provides a unique paradigm to explore intra-cellular differences in chromatin configuration. So far, the detailed allele-specific chromatin organization of imprinted gene domains has mostly been lacking. Here, we explored the chromatin structure of the two conserved imprinted domains controlled by paternal DNA methylation imprints—the Igf2-H19 and Dlk1-Dio3 domains—and assessed the involvement of the insulator protein CTCF in mouse cells.ResultsBoth imprinted domains are located within overarching topologically associating domains (TADs) that are similar on both parental chromosomes. At each domain, a single differentially methylated region is bound by CTCF on the maternal chromosome only, in addition to multiple instances of bi-allelic CTCF binding. Combinations of allelic 4C-seq and DNA-FISH revealed that bi-allelic CTCF binding alone, on the paternal chromosome, correlates with a first level of sub-TAD structure. On the maternal chromosome, additional CTCF binding at the differentially methylated region adds a further layer of sub-TAD organization, which essentially hijacks the existing paternal-specific sub-TAD organization. Perturbation of maternal-specific CTCF binding site at the Dlk1-Dio3 locus, using genome editing, results in perturbed sub-TAD organization and bi-allelic Dlk1 activation during differentiation.ConclusionsMaternal allele-specific CTCF binding at the imprinted Igf2-H19 and the Dlk1-Dio3 domains adds an additional layer of sub-TAD organization, on top of an existing three-dimensional configuration and prior to imprinted activation of protein-coding genes. We speculate that this allele-specific sub-TAD organization provides an instructive or permissive context for imprinted gene activation during development.

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Epigenetic control and genomic imprinting dynamics of the Dlk1-Dio3 domain

Weinberg-Shukron,

Youngson,

Ferguson-Smith

et al. 2023

Front. Cell Dev. Biol.

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Genomic imprinting is an epigenetic process whereby genes are monoallelically expressed in a parent-of-origin-specific manner. Imprinted genes are frequently found clustered in the genome, likely illustrating their need for both shared regulatory control and functional inter-dependence. The Dlk1-Dio3 domain is one of the largest imprinted clusters. Genes in this region are involved in development, behavior, and postnatal metabolism: failure to correctly regulate the domain leads to Kagami–Ogata or Temple syndromes in humans. The region contains many of the hallmarks of other imprinted domains, such as long non-coding RNAs and parental origin-specific CTCF binding. Recent studies have shown that the Dlk1-Dio3 domain is exquisitely regulated via a bipartite imprinting control region (ICR) which functions differently on the two parental chromosomes to establish monoallelic expression. Furthermore, the Dlk1 gene displays a selective absence of imprinting in the neurogenic niche, illustrating the need for precise dosage modulation of this domain in different tissues. Here, we discuss the following: how differential epigenetic marks laid down in the gametes cause a cascade of events that leads to imprinting in the region, how this mechanism is selectively switched off in the neurogenic niche, and why studying this imprinted region has added a layer of sophistication to how we think about the hierarchical epigenetic control of genome function.

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CTCF controls imprinted gene activity at the mouseDlk1-Dio3andIgf2-H19domains by modulating allele-specific sub-TAD structure

Cited by 3 publications

References 53 publications

Methods for mapping 3D chromosome architecture

Methods for mapping 3D chromosome architecture

CTCF modulates allele-specific sub-TAD organization and imprinted gene activity at the mouse Dlk1-Dio3 and Igf2-H19 domains

Epigenetic control and genomic imprinting dynamics of the Dlk1-Dio3 domain

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