The emerging role of chromatin remodelers in neurodevelopmental disorders: a developmental perspective

Abstract

Neurodevelopmental disorders (NDDs), including intellectual disability (ID) and autism spectrum disorders (ASD), are a large group of disorders in which early insults during brain development result in a wide and heterogeneous spectrum of clinical diagnoses. Mutations in genes coding for chromatin remodelers are overrepresented in NDD cohorts, pointing towards epigenetics as a convergent pathogenic pathway between these disorders. In this review we detail the role of NDD-associated chromatin remodelers during the developmental continuum of progenitor expansion, differentiation, cell-type specification, migration and maturation. We discuss how defects in chromatin remodelling during these early developmental time points compound over time and result in impaired brain circuit establishment. In particular, we focus on their role in the three largest cell populations: glutamatergic neurons, GABAergic neurons, and glia cells. An in-depth understanding of the spatiotemporal role of chromatin remodelers during neurodevelopment can contribute to the identification of molecular targets for treatment strategies.

Keywords: Chromatin accessibility; Epigenetics; Neural progenitor; Neurodevelopment; Radial glia; Transcriptional regulation.

Fig. 1

Left panel: The genome is organised into euchromatic (accessible) or heterochromatic (inaccessible) chromosome territories. Within chromosome territories, large chromatin domains are organised into smaller and smaller sub-domains known as topologically associated domains (TADs). TADs are regions where DNA is highly organised in 3D space to enable long-range transcriptional regulation between non-linearly neighbouring strands. Right panel: DNA is wrapped around an octamer of histones, of which its accessibility is regulated by histone modifications like methylation (Me), Acetylation (Ac) or Ubiquitination (Ub) or by histone modifying enzymes. Finally, transcription can be regulated by direct DNA modifications, such as DNA methylation

Fig. 2

a Developmental timeline of the neocortex (top), with the generation times of the three most important cell classes indicated: Glutamatergic neuron generation in the cortical plate, glia production in the Medial Ganglionic Eminence (MGE) and cortical plate, and GABAergic neuron production in the Ganglionic Eminences (GEs). The timeline is based on mouse cortical development (indicated at the bottom as embryonal days (E), a mouse pregnancy lasts 19.5 days on average), with approximate human weeks post conception (W) displayed for reference. b The effect of chromatin remodelling defects on each cell population, with representative examples chosen from the NDD genes described in this review. Top four panels, defects in CHD family members (Chromodomain Helicase DNA Binding Protein), Setdb1/Ezh2, and BAF complex members on glutamatergic cell generation and maturation. Middle panel, comparable effects of mutations in two different chromatin remodelers on the generation of MGE-derived PV + and SST + neurons. Bottom panel, opposite effect of mutations in different chromatin remodelers on astrocyte generation timing