Autism-associated CHD8 controls reactive gliosis and neuroinflammation via remodeling chromatin in astrocytes
Platon Megagiannis, Mei Yuan, Rachel Yan, Lin Yuan, Jonathan J. Wilde, Hailey Eckersberg, Rahul Suresh, Xinzhu Tan, Hong Chen, W. Todd Farmer, Kuwook Cha, Phuong Uyen Le, Hélène Catoire, Daniel Rochefort, Tony Kwan, Brian A. Yee, Patrick A. Dion, Arjun Krishnaswamy, Jean‐François Cloutier, Stefano Stifani, Kevin Petrecca, G Yeo, Keith K. Murai, Guoping Feng, Guy A. Rouleau, Trey Ideker, Neville E. Sanjana, Yang Zhou
Abstract
Reactive changes of glial cells during neuroinflammation impact brain disorders and disease progression. Elucidating the mechanisms that control reactive gliosis may help us to understand brain pathophysiology and improve outcomes. Here, we report that adult ablation of autism spectrum disorder (ASD)-associated CHD8 in astrocytes attenuates reactive gliosis via remodeling chromatin accessibility, changing gene expression. Conditional Chd8 deletion in astrocytes, but not microglia, suppresses reactive gliosis by impeding astrocyte proliferation and morphological elaboration. Astrocyte Chd8 ablation alleviates lipopolysaccharide-induced neuroinflammation and septic-associated hypothermia in mice. Astrocytic CHD8 plays an important role in neuroinflammation by altering the chromatin landscape, regulating metabolic and lipid-associated pathways, and astrocyte-microglia crosstalk. Moreover, we show that reactive gliosis can be directly mitigated in vivo using an adeno-associated virus (AAV)-mediated Chd8 gene editing strategy. These findings uncover a role of ASD-associated CHD8 in the adult brain, which may warrant future exploration of targeting chromatin remodelers in reactive gliosis and neuroinflammation in injury and neurological diseases.