Chromatin Remodeling Proteins in Epilepsy: Lessons From CHD2-Associated Epilepsy

Abstract

The chromodomain helicase DNA-binding (CHD) family of proteins are ATP-dependent chromatin remodelers that contribute to the reorganization of chromatin structure and deposition of histone variants necessary to regulate gene expression. CHD proteins play an important role in neurodevelopment, as pathogenic variants in CHD1, CHD2, CHD4, CHD7 and CHD8 have been associated with a range of neurological phenotypes, including autism spectrum disorder (ASD), intellectual disability (ID) and epilepsy. Pathogenic variants in CHD2 are associated with developmental epileptic encephalopathy (DEE) in humans, however little is known about how these variants contribute to this disorder. Of the nine CHD family members, CHD2 is the only one that leads to a brain-restricted phenotype when disrupted in humans. This suggests that despite being expressed ubiquitously, CHD2 has a unique role in human brain development and function. In this review, we will discuss the phenotypic spectrum of patients with pathogenic variants in CHD2, current animal models of CHD2 deficiency, and the role of CHD2 in proliferation, neurogenesis, neuronal differentiation, chromatin remodeling and DNA-repair. We also consider how CHD2 depletion can affect each of these biological mechanisms and how these defects may underpin neurodevelopmental disorders including epilepsy.

Keywords: CHD2; chromatin remodeler; epigenetics; epilepsy genetics; neurodevelopment.

Figure 1

Distribution of chromodomain helicase DNA-binding (CHD)2 pathogenic variants. CHD2 protein schematic showing functional domains and locations of genetic variants. Putative functional domains include two chromodomains, two helicase domains, and a DNA-binding region. The C-terminus of CHD2 also associates with a poly ADP-ribose (PAR) binding domain that is involved in DNA damage repair (Luijsterburg et al., 2016). Pathogenic CHD2 variants identified in patients with epilepsy and neurodevelopmental disorders (top panel) include truncating variants (red vertical lines denote amino acid position) throughout the protein, and missense variants located in the helicase domains (n = 5) and in the C-terminus (n = 2). This region of the C-terminus is of unknown function, however the presence of 2 missense variants in patients with developmental epileptic encephalopathy (DEE) suggest this region is important for tertiary structure and/or CHD2 function (Pinto et al., , ; Capelli et al., ; Neale et al., ; Rauch et al., ; Carvill et al., ; Suls et al., ; Chenier et al., ; Courage et al., ; Hamdan et al., ; Lund et al., ; O’Roak et al., ; Fitzgerald et al., ; Galizia et al., ; Thomas et al., ; Trivisano et al., ; Helbig et al., ; Lebrun et al., ; Wang et al., ; Ko et al., ; Rim et al., ; Zhou et al., 2018). The chromodomains, helicase domains and DNA-binding domain are depleted of missense variation in the general population as indicated by missense variants present more than twice in the GnomAD dataset (black vertical lines, bottom panel; Lek et al., 2016).

Figure 2

Role of CHD2 in differentiation of excitatory and inhibitory neurons. (A) A schematic representation of a coronal section of one half of an embryonic forebrain showing the subdivisions of the telencephalic proliferative zones: lateral ganglionic eminence (LGE) and medial ganglionic eminence (MGE). Excitatory neurons are born in the ventricular zone (VZ) of the cortex and migrate toward the brain surface (blue arrows). Most inhibitory interneurons of the cortex originate in the MGE and LGE, migrating tangentially to colonize the cortex (yellow arrows). Biallelic knockdown of CHD2 in vitro has been shown to impair interneuron development. In vivo, CHD2 loss may hypothetically result in fewer interneurons migrating from the MGE/LGE or immature interneurons in the forebrain (B) Following migration to the cortex, GABAergic inhibitory interneurons (yellow) follow either a superficial migratory stream through the cortical plate (CP) and marginal zone (MZ) or migrate through the deep layers of the subventricular (SZ) and intermediate zones (IZ). In early stages of development, radial glial cells (RGCs; green) divide symmetrically to produce two new RGCs and replenish the progenitor pool (represented by circular arrow). As development progresses, Pax6+ RGCs begin to divide asymmetrically in the VZ, giving rise to excitatory neurons (shades of blue) or Tbr2+ intermediate progenitors (IPs; pink). Chd2 is expressed primarily in RGCs in the VZ/SVZ and is not expressed in IPs. When Chd2 is disrupted, self-renewal of RGCs is diminished, there is an increase in the production of IPs, and more cells differentiate into glutamatergic neurons (red arrows; Anderson et al., ; Kriegstein and Noctor, ; Wu et al., ; Shen et al., 2015). CP, cortical plate; IZ, intermediate zone; LGE, lateral ganglionic eminence; MGE, medial ganglionic eminence; MZ, marginal zone; SP, subplate; SVZ, subventricular zone; VZ, ventricular zone.

Figure 3

Model for CHD2 role in chromatin remodeling and epilepsy. (A) During development, CHD2 is recruited to poised promoters with the bivalent histone modifications, H3K27me3 (repressive) and H3K4me3 (activating) by interaction with specific transcription factors. CHD2 remodels chromatin at target genes by replacing histone H3 with H3.3 and creating a more permissive chromatin state whereby transcription of developmental genes can occur during differentiation. (B) When CHD2 is mutated, promoters that would normally be poised for differentiation have an increase in the repressive H3K27me3 histone modification and H3.3 is not incorporated. These changes in the chromatin architecture restrict the expression of target genes during differentiation. During neuronal development this pathogenic mechanism likely leads to reduced expression of genes important in neuronal differentiation and impairments that ultimately lead to epilepsy and associated neurodevelopmental disorders.