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

Baptiste Brulé, Rafael Alcalá-Vida, Noémie Penaud, Jil Scuto, Coline Mounier, Jonathan Seguin, Sina Vincent Khodaverdian, Brigitte Cosquer, Etienne Birmelé, Stéphanie Gras, Charles Decraene, Anne-Laurence Boutillier and Karine Merienne ()
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Baptiste Brulé: Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA)
Rafael Alcalá-Vida: Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA)
Noémie Penaud: Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA)
Jil Scuto: Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA)
Coline Mounier: Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA)
Jonathan Seguin: Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA)
Sina Vincent Khodaverdian: University of Strasbourg
Brigitte Cosquer: Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA)
Etienne Birmelé: University of Strasbourg
Stéphanie Gras: University of Strasbourg
Charles Decraene: Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA)
Anne-Laurence Boutillier: Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA)
Karine Merienne: Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA)

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-56722-z

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