CHD8, or Chromodomain Helicase DNA-binding 8, is a transcriptional regulator expressed in nearly all cell types [3]. It is implicated in multiple cellular processes such as cell cycle, cell adhesion, neuronal development, myelination, and synaptogenesis [3]. Mutations in CHD8 are strongly associated with autism spectrum disorder (ASD), and it is also the genetic cause of a distinct neurodevelopmental syndrome with core symptoms of autism, macrocephaly, and facial dysmorphism [4]. Animal models, especially gene-knockout (KO) mouse models, have been crucial in understanding its functions [3,4].

In human cerebral organoids, CHD8 haploinsufficiency disrupted neurodevelopmental trajectories, accelerating inhibitory neuron generation and delaying excitatory neuron generation, leading to an imbalance that may relate to macrocephaly seen in patients [1]. Disruptive CHD8 mutations in zebrafish recapitulate human phenotypes like increased head size due to forebrain/midbrain expansion and impaired gastrointestinal motility [2]. In mice, adult ablation of CHD8 in astrocytes attenuates reactive gliosis and alleviates neuroinflammation, suggesting its role in regulating chromatin accessibility and gene expression in astrocytes [5].

In conclusion, CHD8 plays essential roles in neurodevelopment, with its disruption linked to ASD and other neurodevelopmental phenotypes. Studies using KO or conditional knockout (CKO) mouse models and other organisms have revealed its functions in neuronal development, brain-gut axis regulation, and reactive gliosis and neuroinflammation control, contributing to our understanding of the mechanisms underlying these disease-related processes [1,2,5].

References:

1. Villa, Carlo Emanuele, Cheroni, Cristina, Dotter, Christoph P, Testa, Giuseppe, Novarino, Gaia. . CHD8 haploinsufficiency links autism to transient alterations in excitatory and inhibitory trajectories. In Cell reports, 39, 110615. doi:10.1016/j.celrep.2022.110615. https://pubmed.ncbi.nlm.nih.gov/35385734/

2. Bernier, Raphael, Golzio, Christelle, Xiong, Bo, Katsanis, Nicholas, Eichler, Evan E. 2014. Disruptive CHD8 mutations define a subtype of autism early in development. In Cell, 158, 263-276. doi:10.1016/j.cell.2014.06.017. https://pubmed.ncbi.nlm.nih.gov/24998929/

3. Weissberg, Orly, Elliott, Evan. 2021. The Mechanisms of CHD8 in Neurodevelopment and Autism Spectrum Disorders. In Genes, 12, . doi:10.3390/genes12081133. https://pubmed.ncbi.nlm.nih.gov/34440307/

4. Hoffmann, Anke, Spengler, Dietmar. 2021. Chromatin Remodeler CHD8 in Autism and Brain Development. In Journal of clinical medicine, 10, . doi:10.3390/jcm10020366. https://pubmed.ncbi.nlm.nih.gov/33477995/

5. Megagiannis, Platon, Mei, Yuan, Yan, Rachel E, Sanjana, Neville E, Zhou, Yang. 2024. Autism-associated CHD8 controls reactive gliosis and neuroinflammation via remodeling chromatin in astrocytes. In Cell reports, 43, 114637. doi:10.1016/j.celrep.2024.114637. https://pubmed.ncbi.nlm.nih.gov/39154337/