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

Author:

Llères David,Moindrot Benoît,Pathak Rakesh,Piras VincentORCID,Matelot Mélody,Pignard Benoît,Marchand Alice,Poncelet Mallory,Perrin Aurélien,Tellier Virgile,Feil RobertORCID,Noordermeer DaanORCID

Abstract

SUMMARYMammalian genomic imprinting is essential for development and provides a unique paradigm to explore intra-cellular differences in chromatin configuration. Here, we compared chromatin structure of the two conserved imprinted domains controlled by paternal DNA methylation imprints—the Igf2-H19 and the Dlk1-Dio3 domains—and assessed the involvement of the insulator protein CTCF. At both domains, CTCF binds the maternal allele of a differentially-methylated region (DMR), in addition to multiple instances of bi-allelic CTCF binding in their surrounding TAD (Topologically Associating Domain). On the paternal chromosome, bi-allelic CTCF binding alone is sufficient to structure a first level of sub-TAD organization. Maternal-specific CTCF binding at the DMRs adds a further layer of sub-TAD organization, which essentially hijacks the existing paternal sub-TAD organisation. Genome-editing experiments at the Dlk1-Dio3 locus confirm that the maternal sub-TADs are essential during development to maintain the imprinted Dlk1 gene in an inactive state on the maternal chromosome.

Publisher

Cold Spring Harbor Laboratory

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