Kdm1a Safeguards the Topological Boundaries of PRC2-repressed Genes and Prevents Aging-related Euchromatinization in Neurons

Overview

Journal Nat Commun

Specialty Biology

Date 2024 Mar 7

PMID 38453932

Authors

Beatriz Del Blanco

Sergio Ninerola

Ana M Martin-Gonzalez

Juan Paraiso-Luna

Minji Kim

Rafael Munoz-Viana

Carina Racovac

Jose V Sanchez-Mut

Yijun Ruan

Angel Barco

Affiliations

Soon will be listed here.

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.

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