Cell Reports (Aug 2024)
Autism-associated CHD8 controls reactive gliosis and neuroinflammation via remodeling chromatin in astrocytes
- Platon Megagiannis,
- Yuan Mei,
- Rachel E. Yan,
- Lin Yuan,
- Jonathan J. Wilde,
- Hailey Eckersberg,
- Rahul Suresh,
- Xinzhu Tan,
- Hong Chen,
- W. Todd Farmer,
- Kuwook Cha,
- Phuong Uyen Le,
- Helene Catoire,
- Daniel Rochefort,
- Tony Kwan,
- Brian A. Yee,
- Patrick Dion,
- Arjun Krishnaswamy,
- Jean-Francois Cloutier,
- Stefano Stifani,
- Kevin Petrecca,
- Gene W. Yeo,
- Keith K. Murai,
- Guoping Feng,
- Guy A. Rouleau,
- Trey Ideker,
- Neville E. Sanjana,
- Yang Zhou
Affiliations
- Platon Megagiannis
- Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, Canada
- Yuan Mei
- Division of Genetics, Department of Medicine, University of California, San Diego, San Diego, CA, USA; Department of Cellular and Molecular Medicine, Stem Cell Program, Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA, USA
- Rachel E. Yan
- New York Genome Center, New York, NY, USA; Department of Biology, New York University, New York, NY, USA
- Lin Yuan
- Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, Canada
- Jonathan J. Wilde
- Department of Brain and Cognitive Sciences, McGovern Institute for Brain Research, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Hailey Eckersberg
- Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, Canada
- Rahul Suresh
- Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, Canada
- Xinzhu Tan
- Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, Canada
- Hong Chen
- Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, Canada
- W. Todd Farmer
- Centre for Research in Neuroscience, Department of Neurology and Neurosurgery, Brain Repair and Integrative Neuroscience Program, The Research Institute of the McGill University Health Center, Montreal General Hospital, Montreal, QC, Canada
- Kuwook Cha
- Department of Physiology, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, Canada
- Phuong Uyen Le
- Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, Canada
- Helene Catoire
- Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, Canada
- Daniel Rochefort
- Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, Canada
- Tony Kwan
- McGill Genome Center and Department of Human Genetics, McGill University, Montreal, QC, Canada
- Brian A. Yee
- Department of Cellular and Molecular Medicine, Stem Cell Program, Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA, USA
- Patrick Dion
- Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, Canada
- Arjun Krishnaswamy
- Department of Physiology, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, Canada
- Jean-Francois Cloutier
- Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, Canada
- Stefano Stifani
- Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, Canada
- Kevin Petrecca
- Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, Canada
- Gene W. Yeo
- Department of Cellular and Molecular Medicine, Stem Cell Program, Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA, USA
- Keith K. Murai
- Centre for Research in Neuroscience, Department of Neurology and Neurosurgery, Brain Repair and Integrative Neuroscience Program, The Research Institute of the McGill University Health Center, Montreal General Hospital, Montreal, QC, Canada
- Guoping Feng
- Department of Brain and Cognitive Sciences, McGovern Institute for Brain Research, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Guy A. Rouleau
- Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, Canada
- Trey Ideker
- Division of Genetics, Department of Medicine, University of California, San Diego, San Diego, CA, USA; Corresponding author
- Neville E. Sanjana
- New York Genome Center, New York, NY, USA; Department of Biology, New York University, New York, NY, USA
- Yang Zhou
- Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, Canada; Corresponding author
- Journal volume & issue
-
Vol. 43,
no. 8
p. 114637
Abstract
Summary: 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.
