Autism-associated CHD8 controls reactive gliosis and neuroinflammation via remodeling chromatin in astrocytes
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.
Authors
- Keith K. Murai (ORCID: https://orcid.org/0000-0002-5313-1106)
- Rachel Yan (ORCID: https://orcid.org/0000-0002-6718-142X)
- Guy Armand Rouleau (ORCID: https://orcid.org/0000-0001-8403-1418)
- Jean‐François Cloutier (ORCID: https://orcid.org/0000-0003-0840-2795)
- Guoping Feng (ORCID: https://orcid.org/0000-0002-8021-277X)
- Neville E. Sanjana (ORCID: https://orcid.org/0000-0002-1504-0027)
- Xinzhu Tan
- Kevin Petrecca (ORCID: https://orcid.org/0000-0002-8140-6402)
- Platon Megagiannis (ORCID: https://orcid.org/0000-0003-0282-6730)
- W. Todd Farmer (ORCID: https://orcid.org/0000-0001-8042-9840)
- Tony Kwan (ORCID: https://orcid.org/0000-0001-8929-2334)
- Yang Zhou (ORCID: https://orcid.org/0000-0003-3072-271X)
- Brian A. Yee (ORCID: https://orcid.org/0000-0001-5615-8550)
- Rahul Suresh (ORCID: https://orcid.org/0000-0002-0805-261X)
- Patrick A. Dion (ORCID: https://orcid.org/0000-0002-2099-954X)
- Kuwook Cha
- Hélène Catoire
- Jonathan J. Wilde (ORCID: https://orcid.org/0000-0002-0800-8854)
- Daniel Rochefort
- G Yeo
- Stefano Stifani (ORCID: https://orcid.org/0000-0002-2376-7701)
- Trey Ideker (ORCID: https://orcid.org/0000-0002-1708-8454)
- Arjun Krishnaswamy (ORCID: https://orcid.org/0000-0002-7706-4657)
- Hong Chen (ORCID: https://orcid.org/0000-0001-7799-4961)
- Mei Yuan (ORCID: https://orcid.org/0009-0005-3905-4342)
- Yuan Lin (ORCID: https://orcid.org/0000-0002-6974-8856)
- Hailey Eckersberg
- Phuong Uyen Le
Institutions
- Montreal General Hospital (CA)
- McGill University Health Centre (CA)
- University of California San Diego (US)
- New York Genome Center (US)
- McGill University (CA)
Publication Details
- Journal
- Cell Reports
- Published
- 2024-08-01
- DOI
- https://doi.org/10.1016/j.celrep.2024.114637
- Citations
- 17
- Primary Topic
- Genetics and Neurodevelopmental Disorders
- Type
- article
- Field-Weighted Citation Impact
- 9.36
Funders
- McGill University
- National Alliance for Research on Schizophrenia and Depression
- Azrieli Foundation
- Hospital for Sick Children
- Canada First Research Excellence Fund
- National Institutes of Health
- Montreal Neurological Institute and Hospital
- Canadian Institutes of Health Research
- Natural Sciences and Engineering Research Council of Canada
- Fonds de Recherche du Québec - Santé
- National Institute of Mental Health
- Centre Azrieli de recherche sur l'autisme, Institut et Hôpital Neurologiques de Montréal