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| Status |
Public on Jan 14, 2023 |
| Title |
Dysregulation of the chromatin environment leads to differential alternative splicing as a mechanism of disease in a human model of autism spectrum disorder |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Autism spectrum disorder (ASD) affects 1 in 44 children. Chromatin regulatory proteins are overrepresented among genes that contain high risk variants in ASD. Disruption of the chromatin environment leads to widespread dysregulation of gene expression, which is traditionally thought of as a mechanism of disease pathogenesis associated with ASD. Alternatively, alterations in chromatin dynamics could also lead to dysregulation of alternative splicing, which is understudied as a mechanism of ASD pathogenesis. The anticonvulsant valproic acid (VPA) is a well-known environmental risk factor for ASD that acts as a class I histone deacetylase (HDAC) inhibitor. However, the precise molecular mechanisms underlying defects in human neuronal development associated with exposure to VPA are understudied. To dissect how VPA exposure and subsequent chromatin hyperacetylation influence molecular signatures involved in ASD pathogenesis, we conducted RNA sequencing (RNA-seq) in human cortical neurons that were treated with VPA. We observed that differentially expressed genes (DEGs) were enriched for mRNA splicing, mRNA processing, histone modification, and metabolism related gene sets. Furthermore, we observed widespread increase in the number and the type of alternative splicing events. Analysis of differential transcript usage (DTU) showed that exposure to VPA induces extensive alterations in transcript isoform usage across neurodevelopmentally important genes. Finally, we find that DEGs and genes that display DTU overlap with known ASD-risk genes. Together, these findings suggest that, in addition to differential gene expression, changes in alternative splicing correlated with alterations in the chromatin environment could act as an additional mechanism of disease in ASD.
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| Overall design |
Bulk RNA-sequencing of human iPSC-derived neurons treated with valproic acid (VPA).
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| Contributor(s) |
Leung CS, Rosenzweig SJ, Yoon B, Marinelli NA, Hollingsworth EW, Maguire AM, Cowen MH, Schmidt M, Imitola J, Gamsiz Uzun ED, Lizarraga SB |
| Citation(s) |
36621967 |
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| Submission date |
Jan 09, 2023 |
| Last update date |
Apr 15, 2023 |
| Contact name |
Calvin S Leung |
| Organization name |
Brown University
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| Department |
MCB
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| Lab |
Laboratories for Molecular Medicine, Room 322B
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| Street address |
70 Ship Street
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| City |
Providence |
| State/province |
RI |
| ZIP/Postal code |
02903 |
| Country |
USA |
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| Platforms (1) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
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| Samples (6)
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| GSM6925115 |
vehicle, iPSC-derived neurons, biol rep 1 |
| GSM6925116 |
vehicle, iPSC-derived neurons, biol rep 2 |
| GSM6925117 |
vehicle, iPSC-derived neurons, biol rep 3 |
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| Relations |
| BioProject |
PRJNA922312 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE222509_RAW.tar |
17.0 Mb |
(http)(custom) |
TAR (of TXT) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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