Genetic and epigenetic regulation of Treg cell fitness by autism-related chromatin remodeler CHD8

Chromatin remodeler CHD8 defines a subtype of autism. Its role in regulatory T cells (Tregs) that maintain immune tolerance through suppressing CD4+ and CD8+ effector T cells remain unknown. In this study, we found that Treg-specific CHD8 deletion led to early, fatal inflammatory disorders, due to increased CD4+ and CD8+ effector T cells. CHD8 deletion increased Treg plasticity as evidenced by elevated effector T cell cytokine expression in Tregs. CHIP-seq uncovered that CHD8 binding genes were enriched in PI3K-Akt-mTOR signaling and several other pathways. RNA-seq and ATAC-seq revealed that CHD8 deletion upregulated a number of pathways, notably mTORC1 signaling and its mediated glycolysis that have been reported to promote Treg plasticity. Integrating RNA-seq data with ATAC-seq and/or CHIP-seq data indicates that CHD8 regulates gene expression in either chromatin remodeling- and/or CHD8 binding-dependent or -independent manner. Collectively, our findings suggest that CHD8 plays an important role in maintaining Treg fitness via genetic and epigenetic mechanisms. Yang et al. demonstrate that autism-related CHD8 is important for maintaining Treg cell fitness by controlling gene expression and chromatin remodeling in CHD8 binding-dependent or -independent manner.In this study, in order to investigate the effects of CHD8 on Tregs, we conditionally deleted CHD8 in Tregs using the Foxp3-YFP/Cre driver. We found that loss of CHD8 dampened Treg fitness, which was associated with genetic and epigenetic alterations, leading to early, fatal, effector T cell-mediated inflammation. We used RNA-seq, ChIP seq and ATAC seq to investigate the molecular changes upon the Treg disregulation