{
  "abstract": "Prader-Willi syndrome (PWS) is a neurodevelopmental disorder caused by loss of expression from the active paternal allele at an imprinted cluster on chromosome 15. Current treatments address individual symptoms rather than the underlying cause of disease. Because all patients preserve a normal but epigenetically silenced maternal copy of these genes, activation of this copy offers a potential disease-modifying therapy. Here, we investigated the epigenetic regulator SMCHD1. First, we demonstrated that SMCHD1 represses the PWS locus in both mice and humans, supporting its relevance as a therapeutic target. Second, we found that SMCHD1 represses the entire PWS locus in neural lineages, extending its previously known role beyond only part of the cluster. Deleting Smchd1 after early development in vivo activated PWS genes in disease-relevant mouse tissues including hypothalamus and improved phenotypes in a PWS mouse model. Despite broader genome-wide binding, postearly development targeting of SMCHD1 appeared remarkably safe, supporting its potential for gene activation therapy for PWS.",
  "abstract_shown": true,
  "affiliations": [
    "The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, VIC, Australia.",
    "Department of Medical Biology, University of Melbourne, Melbourne 3010, VIC, Australia.",
    "Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.",
    "Department of Diabetes, Monash University, Clayton, VIC, Australia.",
    "Monash Institute of Pharmaceutical Sciences, Parkville, VIC, Australia."
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 14,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Megan Iminitoff",
      "orcid": "0009-0005-0513-3392"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Anna Le Fevre",
      "orcid": "0000-0001-5843-9516"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Tamara Cameron",
      "orcid": "0000-0002-1125-1871"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Hannah K. Vanyai",
      "orcid": "0000-0001-7761-0606"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Caleb Chew",
      "orcid": "0009-0000-7747-0367"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Sarah A. Kinkel"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Kelsey Breslin",
      "orcid": "0000-0003-4616-8215"
    },
    {
      "affs": [
        2
      ],
      "name": "Susanne Theiß"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Quentin Gouil",
      "orcid": "0000-0002-5142-7886"
    },
    {
      "affs": [
        3
      ],
      "name": "Merlin Thomas"
    },
    {
      "affs": [
        0,
        1,
        4
      ],
      "name": "James M. Murphy",
      "orcid": "0000-0003-0195-3949"
    },
    {
      "affs": [
        2
      ],
      "name": "Christian P. Schaaf"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Andrew Keniry",
      "orcid": "0000-0002-4061-9540"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Marnie E. Blewitt",
      "orcid": "0000-0002-2984-1474"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/41kwg65qgxdca.bib",
  "cited_by": 0,
  "doi": "10.1126/sciadv.aej5702",
  "fulltext_url": null,
  "id": "41kwg65qgxdca",
  "issns": [
    "2375-2548"
  ],
  "landing_url": "https://www.science.org/doi/10.1126/sciadv.aej5702",
  "language": null,
  "licence": "CC-BY-NC",
  "licence_label": "CC BY-NC",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by-nc/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1311|Genetic Syndromes and Imprinting"
    ]
  ],
  "openalex": "W7221145388",
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-09",
  "publisher": "American Association for the Advancement of Science (AAAS)",
  "ris": "https://research.draconitic.com/paper/41kwg65qgxdca.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:41Z",
      "native_id": "10.1126/sciadv.aej5702",
      "source": "crossref",
      "url": "https://www.science.org/doi/10.1126/sciadv.aej5702"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:1311|Genetic Syndromes and Imprinting",
      "subfield": "genetics-genomics"
    }
  ],
  "title": "SMCHD1 is a target for gene activation therapy to treat Prader-Willi syndrome",
  "title_text": "SMCHD1 is a target for gene activation therapy to treat Prader-Willi syndrome",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:17:41Z",
  "url": "https://research.draconitic.com/paper/41kwg65qgxdca",
  "venue": "Science Advances",
  "versions": []
}