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Naveh NSS , Deegan DF , Huhn J , Traxler E , Lan Y , Weksberg R , Ganguly A , Engel N , Kalish JM
The role of CTCF in the organization of the centromeric 11p15 imprinted domain interactome
Nucleic Acids Res. 2021 Jun 21;49(11) :6315-6330
PMID: 34107024    PMCID: PMC8216465    URL: https://www.ncbi.nlm.nih.gov/pubmed/34107024
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DNA methylation, chromatin-binding proteins, and DNA looping are common components regulating genomic imprinting which leads to parent-specific monoallelic gene expression. Loss of methylation (LOM) at the human imprinting center 2 (IC2) on chromosome 11p15 is the most common cause of the imprinting overgrowth disorder Beckwith-Wiedemann Syndrome (BWS). Here, we report a familial transmission of a 7.6 kB deletion that ablates the core promoter of KCNQ1. This structural alteration leads to IC2 LOM and causes recurrent BWS. We find that occupancy of the chromatin organizer CTCF is disrupted proximal to the deletion, which causes chromatin architecture changes both in cis and in trans. We also profile the chromatin architecture of IC2 in patients with sporadic BWS caused by isolated LOM to identify conserved features of IC2 regulatory disruption. A strong interaction between CTCF sites around KCNQ1 and CDKN1C likely drive their expression on the maternal allele, while a weaker interaction involving the imprinting control region element may impede this connection and mediate gene silencing on the paternal allele. We present an imprinting model in which KCNQ1 transcription is necessary for appropriate CTCF binding and a novel chromatin conformation to drive allele-specific gene expression.
1362-4962 Naveh, Natali S Sobel Orcid: 0000-0002-7086-9911 Deegan, Daniel F Huhn, Jacklyn Traxler, Emily Lan, Yemin Weksberg, Rosanna Orcid: 0000-0002-6501-4150 Ganguly, Arupa Engel, Nora Kalish, Jennifer M Orcid: 0000-0003-1500-9713 K08 CA193915/CA/NCI NIH HHS/United States Journal Article Nucleic Acids Res. 2021 Jun 21;49(11):6315-6330. doi: 10.1093/nar/gkab475.