1. Kdm1a safeguards the topological boundaries of PRC2-repressed genes and prevents aging-related euchromatinization in neurons
- Author
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Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Ministry of Science and Higher Education (Poland), European Commission, Fundació La Marató de TV3, Generalitat Valenciana, Fundación la Caixa, National Institutes of Health (US), Human Frontier Science Program, Consejo Superior de Investigaciones Científicas (España), Blanco, Beatriz del, Niñerola, Sergio, Martín-Gonzalez, Ana M., Paraíso-Luna, Juan, Kim, Minji, Muñoz-Viana, Rafael, Racovac, Carina, Sánchez-Mut, José Vicente, Ruan, Yijun, Barco, Ángel, Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Ministry of Science and Higher Education (Poland), European Commission, Fundació La Marató de TV3, Generalitat Valenciana, Fundación la Caixa, National Institutes of Health (US), Human Frontier Science Program, Consejo Superior de Investigaciones Científicas (España), Blanco, Beatriz del, Niñerola, Sergio, Martín-Gonzalez, Ana M., Paraíso-Luna, Juan, Kim, Minji, Muñoz-Viana, Rafael, Racovac, Carina, Sánchez-Mut, José Vicente, Ruan, Yijun, and Barco, Ángel
- 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.
- Published
- 2024