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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
Cell reports · 2024 · Vol. 43 (8) · pp. 114637
PubMed DOI PMC Full Text

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.

Publication Types

["Journal Article", "Research Support, N.I.H., Extramural", "Research Support, Non-U.S. Gov't"]

Keywords

["AAV", "ASD-associated gene", "CHD8", "CP: Neuroscience", "CRISPR gene editing", "astrocyte", "brain injury", "chromatin remodeling", "neuroinflammation", "reactive gliosis"]

MeSH Terms

["Animals", "Gliosis", "Astrocytes", "Mice", "Chromatin", "Autism Spectrum Disorder", "Neuroinflammatory Diseases", "Chromatin Assembly and Disassembly", "Microglia", "DNA-Binding Proteins", "Mice, Inbred C57BL", "Lipopolysaccharides", "Humans", "Mice, Knockout", "Male", "Cell Proliferation"]

Funding

U01 MH115747 NIMH NIH HHS (United States)
F32 MH124408 NIMH NIH HHS (United States)
P41 GM103504 NIGMS NIH HHS (United States)

Linked Datasets (3)

GSE271650 GSE via ncbi_elink
GEO

Autism-associated CHD8 controls reactive gliosis and neuroinflammation via remodeling chromatin in astrocytes [bulk RNA-seq]

Mus musculus
36 data files
FileTypeSize
K11_2-2447630_S1_L001_R1_001.fastq RNA-Seq 4.0 GB
K11_2-2447630_S1_L001_R1_001.fastq RNA-Seq 4.0 GB
L12_2-2447631_S2_L001_R1_001.fastq RNA-Seq 1.4 GB
L12_2-2447631_S2_L001_R1_001.fastq RNA-Seq 1.4 GB
M13_2-2447632_S3_L001_R1_001.fastq RNA-Seq 3.0 GB
M13_2-2447632_S3_L001_R1_001.fastq RNA-Seq 3.0 GB
N14_2-2447633_S4_L001_R1_001.fastq RNA-Seq 6.9 GB
N14_2-2447633_S4_L001_R1_001.fastq RNA-Seq 6.9 GB
Yang_Zhou_sample1_2-2136355_S1_L002_R1_001.fastq.gz RNA-Seq 4.4 GB
Yang_Zhou_sample1_2-2136355_S1_L002_R1_001.fastq.gz RNA-Seq 4.4 GB
Yang_Zhou_sample2_2-2136356_S2_L002_R1_001.fastq.gz RNA-Seq 3.1 GB
Yang_Zhou_sample2_2-2136356_S2_L002_R1_001.fastq.gz RNA-Seq 3.1 GB
Yang_Zhou_sample3_2-2136357_S3_L002_R1_001.fastq.gz RNA-Seq 3.5 GB
Yang_Zhou_sample3_2-2136357_S3_L002_R1_001.fastq.gz RNA-Seq 3.5 GB
Yang_Zhou_sample4_2-2136358_S4_L002_R1_001.fastq.gz RNA-Seq 3.1 GB
Yang_Zhou_sample4_2-2136358_S4_L002_R1_001.fastq.gz RNA-Seq 3.1 GB
Yang_Zhou_sample5_2-2136359_S5_L002_R1_001.fastq.gz RNA-Seq 3.1 GB
Yang_Zhou_sample5_2-2136359_S5_L002_R1_001.fastq.gz RNA-Seq 3.1 GB
Yang_Zhou_sample6_2-2136360_S6_L002_R1_001.fastq.gz RNA-Seq 3.2 GB
Yang_Zhou_sample6_2-2136360_S6_L002_R1_001.fastq.gz RNA-Seq 3.2 GB
Yang_Zhou_sample7_2-2136361_S7_L002_R1_001.fastq.gz RNA-Seq 3.2 GB
Yang_Zhou_sample7_2-2136361_S7_L002_R1_001.fastq.gz RNA-Seq 3.2 GB
Yang_Zhou_sample8_2-2136362_S8_L002_R1_001.fastq.gz RNA-Seq 2.8 GB
Yang_Zhou_sample8_2-2136362_S8_L002_R1_001.fastq.gz RNA-Seq 2.8 GB
Zhou_A1_2-2322646_S1_L001_R1_001.fastq.gz RNA-Seq 3.0 GB
Zhou_A1_2-2322646_S1_L001_R1_001.fastq.gz RNA-Seq 3.0 GB
Zhou_B2_2-2322647_S2_L001_R1_001.fastq.gz RNA-Seq 1.5 GB
Zhou_B2_2-2322647_S2_L001_R1_001.fastq.gz RNA-Seq 1.5 GB
Zhou_C3_2-2322648_S3_L001_R1_001.fastq.gz RNA-Seq 1.7 GB
Zhou_C3_2-2322648_S3_L001_R1_001.fastq.gz RNA-Seq 1.7 GB
Zhou_D4_2-2322649_S4_L001_R1_001.fastq.gz RNA-Seq 1.7 GB
Zhou_D4_2-2322649_S4_L001_R1_001.fastq.gz RNA-Seq 1.7 GB
Zhou_E5_2-2322650_S5_L001_R1_001.fastq.gz RNA-Seq 2.2 GB
Zhou_E5_2-2322650_S5_L001_R1_001.fastq.gz RNA-Seq 2.2 GB
Zhou_F6_2-2322701_S6_L001_R1_001.fastq.gz RNA-Seq 2.2 GB
Zhou_F6_2-2322701_S6_L001_R1_001.fastq.gz RNA-Seq 2.2 GB
GSE271651 GSE via ncbi_elink
GEO

Autism-associated CHD8 controls reactive gliosis and neuroinflammation via remodeling chromatin in astrocytes [Microglia RNA-seq]

Mus musculus
18 data files
FileTypeSize
cKO-LPS-1_M_ZHO2261A7-1_S7_L001_R1_001.fastq.gz RNA-Seq 2.6 GB
cKO-LPS-1_M_ZHO2261A7-1_S7_L001_R1_001.fastq.gz RNA-Seq 2.6 GB
cKO-LPS-2_M_ZHO2261A8-1_S8_L001_R1_001.fastq.gz RNA-Seq 3.7 GB
cKO-LPS-2_M_ZHO2261A8-1_S8_L001_R1_001.fastq.gz RNA-Seq 3.7 GB
cKO-LPS-3_M_ZHO2261A9-1_S9_L001_R1_001.fastq.gz RNA-Seq 6.5 GB
cKO-LPS-3_M_ZHO2261A9-1_S9_L001_R1_001.fastq.gz RNA-Seq 6.5 GB
SRR29727685.lite RNA-Seq 834.1 MB
WT-1_M_ZHO2261A1-1_S1_L001_R1_001.fastq.gz RNA-Seq 2.7 GB
WT-1_M_ZHO2261A1-1_S1_L001_R1_001.fastq.gz RNA-Seq 2.7 GB
WT-2_M_ZHO2261A2-1_S2_L001_R1_001.fastq.gz RNA-Seq 2.0 GB
WT-2_M_ZHO2261A2-1_S2_L001_R1_001.fastq.gz RNA-Seq 2.0 GB
WT-3_M_ZHO2261A3-1_S3_L001_R1_001.fastq.gz RNA-Seq 834.1 MB
WT-LPS-1_M_ZHO2261A4-1_S4_L001_R1_001.fastq.gz RNA-Seq 2.9 GB
WT-LPS-1_M_ZHO2261A4-1_S4_L001_R1_001.fastq.gz RNA-Seq 2.9 GB
WT-LPS-2_M_ZHO2261A5-1_S5_L001_R1_001.fastq.gz RNA-Seq 3.9 GB
WT-LPS-2_M_ZHO2261A5-1_S5_L001_R1_001.fastq.gz RNA-Seq 3.9 GB
WT-LPS-3_M_ZHO2261A6-1_S6_L001_R1_001.fastq.gz RNA-Seq 3.2 GB
WT-LPS-3_M_ZHO2261A6-1_S6_L001_R1_001.fastq.gz RNA-Seq 3.2 GB
GSE271652 GSE via ncbi_elink
GEO

Autism-associated CHD8 controls reactive gliosis and neuroinflammation via remodeling chromatin in astrocytes [ATAC-seq]

Mus musculus
18 data files
FileTypeSize
cKOLPS1_C01_ZHO2243A7-1_S7_L002_R1_001.fastq.gz ATAC-seq 3.4 GB
cKOLPS1_C01_ZHO2243A7-1_S7_L002_R1_001.fastq.gz ATAC-seq 3.4 GB
cKOLPS2_C02_ZHO2243A8-1_S8_L002_R1_001.fastq.gz ATAC-seq 3.5 GB
cKOLPS2_C02_ZHO2243A8-1_S8_L002_R1_001.fastq.gz ATAC-seq 3.5 GB
cKOLPS3_C03_ZHO2243A9-1_S9_L002_R1_001.fastq.gz ATAC-seq 3.4 GB
cKOLPS3_C03_ZHO2243A9-1_S9_L002_R1_001.fastq.gz ATAC-seq 3.4 GB
WT1_A01_ZHO2243A1-1_S1_L002_R1_001.fastq.gz ATAC-seq 2.9 GB
WT1_A01_ZHO2243A1-1_S1_L002_R1_001.fastq.gz ATAC-seq 2.9 GB
WT2_A02_ZHO2243A2-1_S2_L002_R1_001.fastq.gz ATAC-seq 3.3 GB
WT2_A02_ZHO2243A2-1_S2_L002_R1_001.fastq.gz ATAC-seq 3.3 GB
WT3_A03_ZHO2243A3-1_S3_L002_R1_001.fastq.gz ATAC-seq 3.2 GB
WT3_A03_ZHO2243A3-1_S3_L002_R1_001.fastq.gz ATAC-seq 3.2 GB
WTLPS1_B01_ZHO2243A4-1_S4_L002_R1_001.fastq.gz ATAC-seq 3.2 GB
WTLPS1_B01_ZHO2243A4-1_S4_L002_R1_001.fastq.gz ATAC-seq 3.2 GB
WTLPS2_B02_ZHO2243A5-1_S5_L002_R1_001.fastq.gz ATAC-seq 3.6 GB
WTLPS2_B02_ZHO2243A5-1_S5_L002_R1_001.fastq.gz ATAC-seq 3.6 GB
WTLPS3_B03_ZHO2243A6-1_S6_L002_R1_001.fastq.gz ATAC-seq 3.5 GB
WTLPS3_B03_ZHO2243A6-1_S6_L002_R1_001.fastq.gz ATAC-seq 3.5 GB

Potentially Related Datasets (3)

These accessions were text-mined from the PMC full text. They may be referenced for comparison, cited from other studies, or otherwise mentioned without being primary data for this paper.

GSE271650 GSE GEO
GEO

Autism-associated CHD8 controls reactive gliosis and neuroinflammation via remodeling chromatin in astrocytes [bulk RNA-seq]

GSE271652 GSE GEO
GEO

Autism-associated CHD8 controls reactive gliosis and neuroinflammation via remodeling chromatin in astrocytes [ATAC-seq]

GSE271651 GSE GEO
GEO

Autism-associated CHD8 controls reactive gliosis and neuroinflammation via remodeling chromatin in astrocytes [Microglia RNA-seq]

Analysis Pipelines (3)

GSE271650 RNA-seq Data Processing 5 steps
RNA-seq geo_data_processing GSE271650
GSE271651 RNA-seq Data Processing 8 steps
RNA-seq geo_data_processing GSE271651
GSE271652 ATAC-seq Data Processing 5 steps
ATAC-seq geo_data_processing GSE271652