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Kdm1a safeguards the topological boundaries of PRC2-repressed genes and prevents aging-related euchromatinization in neurons

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  • Beatriz del Blanco

    (Instituto de Neurociencias (Universidad Miguel Hernández - Consejo Superior de Investigaciones Científicas). Av. Santiago Ramón y Cajal s/n. Sant Joan d’Alacant)

  • Sergio Niñerola

    (Instituto de Neurociencias (Universidad Miguel Hernández - Consejo Superior de Investigaciones Científicas). Av. Santiago Ramón y Cajal s/n. Sant Joan d’Alacant)

  • Ana M. Martín-González

    (Instituto de Neurociencias (Universidad Miguel Hernández - Consejo Superior de Investigaciones Científicas). Av. Santiago Ramón y Cajal s/n. Sant Joan d’Alacant)

  • Juan Paraíso-Luna

    (Instituto de Neurociencias (Universidad Miguel Hernández - Consejo Superior de Investigaciones Científicas). Av. Santiago Ramón y Cajal s/n. Sant Joan d’Alacant
    Universidad Complutense de Madrid)

  • Minji Kim

    (The Jackson laboratory for Genomic Medicine
    University of Michigan)

  • Rafael Muñoz-Viana

    (Instituto de Neurociencias (Universidad Miguel Hernández - Consejo Superior de Investigaciones Científicas). Av. Santiago Ramón y Cajal s/n. Sant Joan d’Alacant
    Bioinformatics Unit, Hospital universitario Puerta de Hierro Majadahonda)

  • Carina Racovac

    (Instituto de Neurociencias (Universidad Miguel Hernández - Consejo Superior de Investigaciones Científicas). Av. Santiago Ramón y Cajal s/n. Sant Joan d’Alacant)

  • Jose V. Sanchez-Mut

    (Instituto de Neurociencias (Universidad Miguel Hernández - Consejo Superior de Investigaciones Científicas). Av. Santiago Ramón y Cajal s/n. Sant Joan d’Alacant)

  • Yijun Ruan

    (The Jackson laboratory for Genomic Medicine
    Zhejiang University)

  • Ángel Barco

    (Instituto de Neurociencias (Universidad Miguel Hernández - Consejo Superior de Investigaciones Científicas). Av. Santiago Ramón y Cajal s/n. Sant Joan d’Alacant)

Abstract

Kdm1a is a histone demethylase linked to intellectual disability with essential roles during gastrulation and the terminal differentiation of specialized cell types, including neurons, that remains highly expressed in the adult brain. To explore Kdm1a’s function in adult neurons, we develop inducible and forebrain-restricted Kdm1a knockouts. By applying multi-omic transcriptome, epigenome and chromatin conformation data, combined with super-resolution microscopy, we find that Kdm1a elimination causes the neuronal activation of nonneuronal genes that are silenced by the polycomb repressor complex and interspersed with active genes. Functional assays demonstrate that the N-terminus of Kdm1a contains an intrinsically disordered region that is essential to segregate Kdm1a-repressed genes from the neighboring active chromatin environment. Finally, we show that the segregation of Kdm1a-target genes is weakened in neurons during natural aging, underscoring the role of Kdm1a safeguarding neuronal genome organization and gene silencing throughout life.

Suggested Citation

  • Beatriz del Blanco & Sergio Niñerola & Ana M. Martín-González & Juan Paraíso-Luna & Minji Kim & Rafael Muñoz-Viana & Carina Racovac & Jose V. Sanchez-Mut & Yijun Ruan & Ángel Barco, 2024. "Kdm1a safeguards the topological boundaries of PRC2-repressed genes and prevents aging-related euchromatinization in neurons," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45773-3
    DOI: 10.1038/s41467-024-45773-3
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