From X-inactivation to neurodevelopment: CHD8-transcription factors (TFs) competitive binding at regulatory regions of CHD8 target genes can contribute to correct neuronal differentiation

Abstract

The chromodomain helicase DNA-binding protein 8 (CHD8) is a chromatin remodeler whose mutation is associated, with high penetrance, with autism. Individuals with CHD8 mutations share common symptoms such as autistic behaviour, cognitive impairment, schizophrenia comorbidity, and phenotypic features such as macrocephaly and facial defects. Chd8-deficient mouse models recapitulate most of the phenotypes seen in the brain and other organs of humans. It is known that CHD8 regulates - directly and indirectly - neuronal, autism spectrum disorder (ASDs)-associated genes and long non-coding RNAs (lncRNAs) genes, which, in turn, regulate fundamental aspects of neuronal differentiation and brain development and function. A major characteristic of CHD8 regulation of gene expression is its non-linear and dosage-sensitive nature. CHD8 mutations appear to affect males predominantly, although the reasons for this observed sex bias remain- unknown. We have recently reported that CHD8 directly regulates X chromosome inactivation (XCI) through the transcriptional control of the Xist long non-coding RNA (lncRNA), the master regulator of mammalian XCI. We identified a role for CHD8 in regulating accessibility at the Xist promoter through competitive binding with transcription factors (TFs) at Xist regulatory regions. We speculate here that CHD8 might also regulate accessibility at neuronal/ASD targets through a similar competitive binding mechanism during neurogenesis and brain development. However, whilst such a model can reconcile the phenotypic differences observed in Chd8 knock-down (KD) vs knock-out (KO) mouse models, explaining the observed CHD8 non-linear dosage-dependent activity, it cannot on its own explain the observed disease sex bias.