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
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.
Linked datasets 3
Autism-associated CHD8 controls reactive gliosis and neuroinflammation via remodeling chromatin in astrocytes [bulk RNA-seq]
Mus musculus
36 data files
| File | Type | Size |
|---|---|---|
| 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 |
| 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 |
| SRR29727661_GSM8381206 | RNA-Seq | 6.9 GB |
| SRR29727662_GSM8381205 | RNA-Seq | 3.0 GB |
| SRR29727663_GSM8381204 | RNA-Seq | 2.2 GB |
| SRR29727664_GSM8381203 | RNA-Seq | 2.2 GB |
| SRR29727665_GSM8381202 | RNA-Seq | 1.7 GB |
| SRR29727666_GSM8381201 | RNA-Seq | 1.4 GB |
| SRR29727667_GSM8381200 | RNA-Seq | 4.0 GB |
| SRR29727668_GSM8381199 | RNA-Seq | 1.7 GB |
| SRR29727669_GSM8381198 | RNA-Seq | 1.5 GB |
| SRR29727670_GSM8381197 | RNA-Seq | 3.0 GB |
| SRR29727671_GSM8381196 | RNA-Seq | 2.8 GB |
| SRR29727672_GSM8381195 | RNA-Seq | 3.2 GB |
| SRR29727673_GSM8381194 | RNA-Seq | 3.1 GB |
| SRR29727674_GSM8381193 | RNA-Seq | 3.1 GB |
| SRR29727675_GSM8381192 | RNA-Seq | 3.2 GB |
| SRR29727676_GSM8381191 | RNA-Seq | 3.1 GB |
| SRR29727677_GSM8381190 | RNA-Seq | 3.5 GB |
| SRR29727678_GSM8381189 | 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_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_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_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 |
| 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_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_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 |
Autism-associated CHD8 controls reactive gliosis and neuroinflammation via remodeling chromatin in astrocytes [Microglia RNA-seq]
Mus musculus
19 data files
| File | Type | Size |
|---|---|---|
| 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-3_M_ZHO2261A9-1_S9_L001_R1_001.fastq.gz | RNA-Seq | 6.5 GB |
| SRR29727679_GSM8381215 | RNA-Seq | 6.5 GB |
| SRR29727680_GSM8381214 | RNA-Seq | 3.7 GB |
| SRR29727681_GSM8381213 | RNA-Seq | 2.6 GB |
| SRR29727682_GSM8381212 | RNA-Seq | 3.2 GB |
| SRR29727683_GSM8381211 | RNA-Seq | 3.9 GB |
| SRR29727684_GSM8381210 | RNA-Seq | 2.9 GB |
| SRR29727685_GSM8381209 | RNA-Seq | 834.0 MB |
| SRR29727685.lite | RNA-Seq | 834.1 MB |
| SRR29727686_GSM8381208 | RNA-Seq | 2.0 GB |
| SRR29727687_GSM8381207 | 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-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-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 |
Autism-associated CHD8 controls reactive gliosis and neuroinflammation via remodeling chromatin in astrocytes [ATAC-seq]
Mus musculus
18 data files
| File | Type | Size |
|---|---|---|
| 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 |
| cKOLPS3_C03_ZHO2243A9-1_S9_L002_R1_001.fastq.gz | ATAC-seq | 3.4 GB |
| SRR29727696_GSM8381224 | ATAC-seq | 3.4 GB |
| SRR29727697_GSM8381223 | ATAC-seq | 3.5 GB |
| SRR29727698_GSM8381221 | ATAC-seq | 3.5 GB |
| SRR29727699_GSM8381219 | ATAC-seq | 3.2 GB |
| SRR29727700_GSM8381218 | ATAC-seq | 3.2 GB |
| SRR29727701_GSM8381220 | ATAC-seq | 3.6 GB |
| SRR29727702_GSM8381222 | ATAC-seq | 3.4 GB |
| SRR29727703_GSM8381217 | ATAC-seq | 3.3 GB |
| SRR29727704_GSM8381216 | 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 |
| 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 |
| 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 |
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.
| Accession | Source | Title |
|---|---|---|
| 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
| Pipeline | Assay | Steps | Dataset |
|---|---|---|---|
| GSE271650 RNA-seq Data Processing geo_data_processing | RNA-seq | 5 | GSE271650 |
| GSE271651 RNA-seq Data Processing geo_data_processing | RNA-seq | 8 | GSE271651 |
| GSE271652 ATAC-seq Data Processing geo_data_processing | ATAC-seq | 5 | GSE271652 |
Funding 3 grants
| Grant | Funder |
|---|---|
| U01 MH115747 | NIMH NIH HHS (United States) |
| F32 MH124408 | NIMH NIH HHS (United States) |
| P41 GM103504 | NIGMS NIH HHS (United States) |