The Autism-Related Protein CHD8 Cooperates with C/EBPb to Regulate Adipogenesis

The gene encoding the chromatin remodeler CHD8 is the most frequently mutated gene in individuals with autism spectrum disorder (ASD). Heterozygous mutations in CHD8 give rise to ASD that is often accompanied by macrocephaly, gastrointestinal complaints, and slender habitus. Whereas most phenotypes of CHD8 haploinsufficiency likely result from delayed neurodevelopment, the mechanism underlying slender habitus has remained unknown. Here we show that CHD8 interacts with C/EBPb and promotes its transactivation activity during adipocyte differentiation. Adipogenesis was impaired in Chd8-deleted preadipocytes, with the up-regulation of C/EBPa and PPARg, two master regulators of this process, being attenuated in the mutant cells. Furthermore, mice with CHD8 ablation specifically in preadipocytes had a markedly reduced white adipose tissue mass. Our findings reveal a new mode of C/EBPb regulation by CHD8 during adipogenesis, with CHD8 deficiency resulting in a defect in the development of white adipose tissue.