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Accelerated epigenetic aging in Huntington’s disease involves polycomb repressive complex 1

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  • Baptiste Brulé

    (Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA)
    Centre National de la Recherche Scientifique (CNRS, UMR 7364)
    University of Strasbourg)

  • Rafael Alcalá-Vida

    (Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA)
    Centre National de la Recherche Scientifique (CNRS, UMR 7364)
    University of Strasbourg
    Instituto de Neurociencias (Universidad Miguel Hernández - Consejo Superior de Investigaciones Científicas). Av. Santiago Ramón y Cajal s/n. Sant Joan d’Alacant)

  • Noémie Penaud

    (Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA)
    Centre National de la Recherche Scientifique (CNRS, UMR 7364)
    University of Strasbourg)

  • Jil Scuto

    (Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA)
    Centre National de la Recherche Scientifique (CNRS, UMR 7364)
    University of Strasbourg)

  • Coline Mounier

    (Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA)
    Centre National de la Recherche Scientifique (CNRS, UMR 7364)
    University of Strasbourg)

  • Jonathan Seguin

    (Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA)
    Centre National de la Recherche Scientifique (CNRS, UMR 7364)
    University of Strasbourg)

  • Sina Vincent Khodaverdian

    (University of Strasbourg
    IRMA)

  • Brigitte Cosquer

    (Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA)
    Centre National de la Recherche Scientifique (CNRS, UMR 7364)
    University of Strasbourg)

  • Etienne Birmelé

    (University of Strasbourg
    IRMA)

  • Stéphanie Gras

    (University of Strasbourg
    Institut de Genetique et de Biologie Moleculaire et Cellulaire
    CNRS UMR7104
    INSERM U1258)

  • Charles Decraene

    (Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA)
    Centre National de la Recherche Scientifique (CNRS, UMR 7364)
    University of Strasbourg)

  • Anne-Laurence Boutillier

    (Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA)
    Centre National de la Recherche Scientifique (CNRS, UMR 7364)
    University of Strasbourg)

  • Karine Merienne

    (Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA)
    Centre National de la Recherche Scientifique (CNRS, UMR 7364)
    University of Strasbourg)

Abstract

Loss of epigenetic information during physiological aging compromises cellular identity, leading to de-repression of developmental genes. Here, we assessed the epigenomic landscape of vulnerable neurons in two reference mouse models of Huntington neurodegenerative disease (HD), using cell-type-specific multi-omics, including temporal analysis at three disease stages via FANS-CUT&Tag. We show accelerated de-repression of developmental genes in HD striatal neurons, involving histone re-acetylation and depletion of H2AK119 ubiquitination and H3K27 trimethylation marks, which are catalyzed by polycomb repressive complexes 1 and 2 (PRC1 and PRC2), respectively. We further identify a PRC1-dependent subcluster of bivalent developmental transcription factors that is re-activated in HD striatal neurons. This mechanism likely involves progressive paralog switching between PRC1-CBX genes, which promotes the upregulation of normally low-expressed PRC1-CBX2/4/8 isoforms in striatal neurons, alongside the down-regulation of predominant PRC1-CBX isoforms in these cells (e.g., CBX6/7). Collectively, our data provide evidence for PRC1-dependent accelerated epigenetic aging in HD vulnerable neurons.

Suggested Citation

  • Baptiste Brulé & Rafael Alcalá-Vida & Noémie Penaud & Jil Scuto & Coline Mounier & Jonathan Seguin & Sina Vincent Khodaverdian & Brigitte Cosquer & Etienne Birmelé & Stéphanie Gras & Charles Decraene , 2025. "Accelerated epigenetic aging in Huntington’s disease involves polycomb repressive complex 1," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56722-z
    DOI: 10.1038/s41467-025-56722-z
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