Document Type
Article
Publication Date
3-7-2024
Original Citation
Del Blanco B,
Niñerola S,
Martín-González A,
Paraíso-Luna J,
Kim M,
Muñoz-Viana R,
Racovac C,
Sanchez-Mut J,
Ruan Y,
Barco Á.
Kdm1a safeguards the topological boundaries of PRC2-repressed genes and prevents aging-related euchromatinization in neurons. Nat Commun. 2024;15(1):1781
Keywords
JGM, Histone Demethylases, Chromatin, Neurons
JAX Source
Nat Commun. 2024;15(1):1781
ISSN
2041-1723
PMID
38453932
DOI
https://doi.org/10.1038/s41467-024-45773-3
Grant
M.K. is supported by the National Institutes of Health (K99-HG011542; R00-HG011542). Both A.B. and Y.R. were supported by the RGP0039/2017 from the Human Frontiers Science Program Organization (HFSPO).
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.
Comments
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