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| Status |
Public on Aug 14, 2024 |
| Title |
Cell type-specific dysregulation of gene expression due to Chd8 loss of function during mouse cortical development [scRNA-seq] |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Disruptive variants in the chromodomain helicase CHD8, which acts as a transcriptional regulator during neurodevelopment, are strongly associated with risk for autism spectrum disorder (ASD). Loss of CHD8 function is hypothesized to perturb gene regulatory networks in the developing brain, thereby contributing to ASD etiology. However, insight into the cell type-specific transcriptional effects of CHD8 loss of function remains limited. We used single-cell and single-nucleus RNA-sequencing to globally profile gene expression and identify dysregulated genes in the embryonic and juvenile wild type and Chd8+/− mouse cortex, respectively. Chd8 and other ASD risk-associated genes showed a convergent expression trajectory that was largely conserved between the mouse and human developing cortex, increasing from the progenitor zones to the cortical plate. Genes associated with risk for neurodevelopmental disorders and genes involved in neuron projection development, chromatin remodeling, signaling, and migration were dysregulated in Chd8+/− embryonic day (E) 12.5 radial glia. Genes implicated in synaptic organization and activity were dysregulated in Chd8+/− postnatal day (P) 25 deep- and upper-layer excitatory neurons, suggesting a delay in synaptic maturation or impaired synaptogenesis due to CHD8 loss of function. Our findings reveal a complex pattern of transcriptional dysregulation in Chd8+/− developing cortex, potentially with distinct biological impacts on progenitors and maturing neurons in the excitatory neuronal lineage.
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| Overall design |
Single-cell RNA-seq (scRNA-seq) was performed on developing cortical (i.e., dorsal telencephalon) tissue from embryonic day (E) 12.5, E14.5, E16.0, and E17.5 litter- and sex-matched pairs of wild type and Chd8+/- embryos.Tissue from four pairs of mice was collected for each time point and processed individually.
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| Contributor(s) |
Yim KM, Baumgartner M, Krenzer M, Rosales-Larios MF, Nottoli T, Muhle RA, Noonan JP, Hill-Terán G |
| Citation(s) |
39185167 |
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| Submission date |
Jul 28, 2024 |
| Last update date |
Aug 27, 2024 |
| Contact name |
James Noonan |
| E-mail(s) |
james.noonan@yale.edu
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| Organization name |
Yale School of Medicine
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| Department |
Genetics
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| Street address |
333 Cedar St
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| City |
New Haven |
| State/province |
CT |
| ZIP/Postal code |
06510 |
| Country |
USA |
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| Platforms (1) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
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| Samples (32)
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| GSM8425529 |
E12.5 dorsal telencephalon, wild type male, scRNA-seq, rep1 |
| GSM8425530 |
E12.5 dorsal telencephalon, wild type male, scRNA-seq, rep2 |
| GSM8425531 |
E12.5 dorsal telencephalon, wild type female, scRNA-seq, rep1 |
| GSM8425532 |
E12.5 dorsal telencephalon, wild type female, scRNA-seq, rep2 |
| GSM8425533 |
E12.5 dorsal telencephalon, Chd8 het male, scRNA-seq, rep1 |
| GSM8425534 |
E12.5 dorsal telencephalon, Chd8 het male, scRNA-seq, rep2 |
| GSM8425535 |
E12.5 dorsal telencephalon, Chd8 het female, scRNA-seq, rep1 |
| GSM8425536 |
E12.5 dorsal telencephalon, Chd8 het female, scRNA-seq, rep2 |
| GSM8425537 |
E14.5 dorsal telencephalon, wild type male, scRNA-seq, rep1 |
| GSM8425538 |
E14.5 dorsal telencephalon, wild type male, scRNA-seq, rep2 |
| GSM8425539 |
E14.5 dorsal telencephalon, wild type female, scRNA-seq, rep1 |
| GSM8425540 |
E14.5 dorsal telencephalon, wild type female, scRNA-seq, rep2 |
| GSM8425541 |
E14.5 dorsal telencephalon, Chd8 het male, scRNA-seq, rep1 |
| GSM8425542 |
E14.5 dorsal telencephalon, Chd8 het male, scRNA-seq, rep2 |
| GSM8425543 |
E14.5 dorsal telencephalon, Chd8 het female, scRNA-seq, rep1 |
| GSM8425544 |
E14.5 dorsal telencephalon, Chd8 het female, scRNA-seq, rep2 |
| GSM8425545 |
E16.0 dorsal telencephalon, wild type male, scRNA-seq, rep1 |
| GSM8425546 |
E16.0 dorsal telencephalon, wild type male, scRNA-seq, rep2 |
| GSM8425547 |
E16.0 dorsal telencephalon, wild type female, scRNA-seq, rep1 |
| GSM8425548 |
E16.0 dorsal telencephalon, wild type female, scRNA-seq, rep2 |
| GSM8425549 |
E16.0 dorsal telencephalon, Chd8 het male, scRNA-seq, rep1 |
| GSM8425550 |
E16.0 dorsal telencephalon, Chd8 het male, scRNA-seq, rep2 |
| GSM8425551 |
E16.0 dorsal telencephalon, Chd8 het female, scRNA-seq, rep1 |
| GSM8425552 |
E16.0 dorsal telencephalon, Chd8 het female, scRNA-seq, rep2 |
| GSM8425553 |
E17.5 dorsal telencephalon, wild type male, scRNA-seq, rep1 |
| GSM8425554 |
E17.5 dorsal telencephalon, wild type male, scRNA-seq, rep2 |
| GSM8425555 |
E17.5 dorsal telencephalon, wild type female, scRNA-seq, rep1 |
| GSM8425556 |
E17.5 dorsal telencephalon, wild type female, scRNA-seq, rep2 |
| GSM8425557 |
E17.5 dorsal telencephalon, Chd8 het male, scRNA-seq, rep1 |
| GSM8425558 |
E17.5 dorsal telencephalon, Chd8 het male, scRNA-seq, rep2 |
| GSM8425559 |
E17.5 dorsal telencephalon, Chd8 het female, scRNA-seq, rep1 |
| GSM8425560 |
E17.5 dorsal telencephalon, Chd8 het female, scRNA-seq, rep2 |
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| Relations |
| BioProject |
PRJNA1141138 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE273271_RAW.tar |
1.1 Gb |
(http)(custom) |
TAR (of MTX, TSV) |
SRA Run Selector |
| Raw data are available in SRA |
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