Bs-515-01 Non-Coding Deletion Induces 3d Chromatin Remodelling and Pitx2 Expression Dysregulation Associated With a Syndromic Cardiac Disorder

Baudic, Manon; Murata, Hiroshige; Bosada, Fernanda M.; Melo, Uira Souto; Ishikawa, Taisuke; Aizawa, Takanori; Guedon, Amaury; Baron, Estelle; FOUCAL, ADRIEN; Livet, Pierre; Scouarnec, Solena Le; Shimizu, Wataru; GOURRAUD, JEAN BAPTISTE; Makita, Naomasa; Marec, Hervé Le; Vieyres, C; Mundlos, S; Christoffels, Vincent M.; Makiyama, Takeru; Probst, Vincent; Schott, Jean‐Jacques; Barc, Julien

doi:10.1016/j.hrthm.2022.03.683

Cited by 2 publications

(1 citation statement)

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“…The loop extrusion model predicts that perturbation of the extrusion machinery, or sequence variants that disrupt CTCF binding, can result in loss of insulation, ectopic enhancerpromoter interactions, and off-target gene activation with potential pathogenic outcomes. Indeed, such effects have been observed in multiple studies (Baudic et al, 2024;Cova et al, 2023;Dowen et al, 2014;Ealo et al, 2023;Engel et al, 2008;Flavahan et al, 2016;Franke et al, 2016;Hanssen et al, 2017;Juan et al, 2022;Kraft et al, 2019;Lupianez et al, 2015;Narendra et al, 2015;Rajderkar et al, 2023;van Bemmel et al, 2019;Wu et al, 2021) . However, disruption of chromatin domains does not always impact gene regulation or affect physiological processes.…”

Section: Introductionmentioning

confidence: 95%

Structural perturbation of chromatin domains with multiple developmental regulators can severely impact gene regulation and development

Chakraborty,

Wenzlitschke,

Anderson

et al. 2024

Preprint

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Chromatin domain boundaries delimited by CTCF motifs can restrict the range of enhancer action. However, disruption of domain structure often results in mild gene dysregulation and thus predicting the impact of boundary rearrangements on animal development remains challenging. Here, we tested whether structural perturbation of a chromatin domain with multiple developmental regulators can result in more acute gene dysregulation and severe developmental phenotypes. We targeted clusters of CTCF motifs in a domain of the mouse genome containing three FGF ligand genes - Fgf3, Fgf4, and Fgf15 - that regulate several developmental processes. Deletion of the 23.9kb cluster that defines the centromeric boundary of this domain resulted in ectopic interactions of the FGF genes with enhancers located across the deleted boundary that are active in the developing brain. This caused strong induction of FGF expression and perinatal lethality with encephalocele and orofacial cleft phenotypes. Heterozygous boundary deletion was sufficient to cause these fully penetrant phenotypes, and strikingly, loss of a single CTCF motif within the cluster also recapitulated ectopic FGF expression and caused encephalocele. However, such phenotypic sensitivity to perturbation of domain structure did not extend to all CTCF clusters of this domain, nor to all developmental processes controlled by these three FGF genes - for example, the ability to undergo lineage specification in the blastocyst and pre-implantation development were not affected. By tracing the impact of different chromosomal rearrangements throughout mouse development, we start to uncover the determinants of phenotypic robustness and sensitivity to perturbation of chromatin boundaries. Our data show how small sequence variants at certain domain boundaries can have a surprisingly outsized effect and must be considered as potential sources of gene dysregulation during development and disease.

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