{
    "abstract": "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.",
    "authors": [
        {
            "affiliation": "Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.",
            "firstname": "Natali S Sobel",
            "initials": "NSS",
            "lastname": "Naveh"
        },
        {
            "affiliation": "Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, PA 19140, USA.",
            "firstname": "Daniel F",
            "initials": "DF",
            "lastname": "Deegan"
        },
        {
            "affiliation": "Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, PA 19140, USA.",
            "firstname": "Jacklyn",
            "initials": "J",
            "lastname": "Huhn"
        },
        {
            "affiliation": "Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.",
            "firstname": "Emily",
            "initials": "E",
            "lastname": "Traxler"
        },
        {
            "affiliation": "Epigenetics Institute, Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.",
            "firstname": "Yemin",
            "initials": "Y",
            "lastname": "Lan"
        },
        {
            "affiliation": "Division of Clinical and Metabolic Genetics,\u00a0Genetics and Genome Biology,\u00a0Hospital for Sick Children, and\u00a0Institute of Medical Science, University of Toronto, Toronto, Canada.",
            "firstname": "Rosanna",
            "initials": "R",
            "lastname": "Weksberg"
        },
        {
            "affiliation": "Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.",
            "firstname": "Arupa",
            "initials": "A",
            "lastname": "Ganguly"
        },
        {
            "affiliation": "Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, PA 19140, USA.",
            "firstname": "Nora",
            "initials": "N",
            "lastname": "Engel"
        },
        {
            "affiliation": "Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.\nDepartment of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.\nDepartment of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.",
            "firstname": "Jennifer M",
            "initials": "JM",
            "lastname": "Kalish"
        }
    ],
    "conclusions": null,
    "copyrights": "\u00a9 The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.",
    "doi": "10.1093/nar/gkab475\n10.1002/0471250953.bi1107s32",
    "journal": "Nucleic acids research",
    "keywords": [],
    "methods": null,
    "publication_date": "2021-06-10",
    "pubmed_id": "34107024\n24757003\n32117048\n22195775\n25023695\n29377879\n31469230\n32039119\n23918458\n22205991\n29223973\n23511928\n19843502\n24154661\n21920939\n30778172\n15372379\n21780245\n23061425\n26839037\n10220444\n9020845\n10393948\n8776593\n8610162\n10369866\n15233993\n16321503\n16702402\n30635621\n25539921\n20573698\n32393365\n28428215\n15516932\n18951091\n24395636\n22085535\n23028363\n25297545\n12461525\n16928784\n16815976\n25002401\n12874112\n21304052\n17242189\n24996904\n24129436\n27200075\n32427849\n32430359\n29092934\n11846609\n22955616\n32728249\n12045153\n23804403\n20110278\n30286773\n19815776\n26595209\n21903629\n21154709\n24561615\n24489365\n24903420\n24930139\n24309898\n21628529\n7550351\n31197269\n32299027\n30664301\n22555596\n15888726\n17084362\n16628224\n15340049\n18079696\n18299392\n15809263\n19144718\n21775415",
    "results": null,
    "title": "The role of CTCF in the organization of the centromeric 11p15 imprinted domain interactome.",
    "xml": "<Element 'PubmedArticle' at 0x788505614f90>"
}