Genetic and epigenetic regulation of Treg cells by autism-related CHD8 2064

Description Chromodomain Helicase DNA-binding (CHD) proteins are crucial regulators of chromatin remodeling, gene transcription and expression. CHD8 of the CHD proteins is involved in many important signaling pathways, such as p53 and Wnt-β-catenin pathways. It remains unclear whether CHD8 plays a role in immune regulatory T cells (Tregs). In this study, Treg-specific conditional CHD8-deficient mice were generated. We found that CHD8 deficiency in Treg led to early, fatal inflammation, due to increased CD4+ and CD8+ effector T cells. CHD8 deletion did not alter Treg homeostasis but increased their activation and promoted functional plasticity with elevated expression of effector T cell cytokines, such as IFN-g, IL-4 and IL-17. CHIP-seq of Tregs 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 multiple 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. Our findings suggest that autism-related CHD8 is important for maintaining Treg fitness, via genetic and epigenetic mechanisms, to control autoimmunity. More in-depth studies are ongoing to further elucidate the underlying molecular mechanisms. Funding Sources This work was supported by NCI (R01CA234038-01A1 and R01CA278756-01A1) awards to F.G. and Y.Z.