Single-cell long-read sequencing in human cerebral organoids uncovers cell-type-specific and autism-associated exons
Summary: Dysregulation of alternative splicing has been repeatedly associated with neurodevelopmental disorders, but the extent of cell-type-specific splicing in human neural development remains largely uncharted. Here, single-cell long-read sequencing in induced pluripotent stem cell (iPSC)-derived...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-11-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124723013475 |
| _version_ | 1797448084166279168 |
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| author | Yalan Yang Runwei Yang Bowei Kang Sheng Qian Xin He Xiaochang Zhang |
| author_facet | Yalan Yang Runwei Yang Bowei Kang Sheng Qian Xin He Xiaochang Zhang |
| author_sort | Yalan Yang |
| collection | DOAJ |
| description | Summary: Dysregulation of alternative splicing has been repeatedly associated with neurodevelopmental disorders, but the extent of cell-type-specific splicing in human neural development remains largely uncharted. Here, single-cell long-read sequencing in induced pluripotent stem cell (iPSC)-derived cerebral organoids identifies over 31,000 uncatalogued isoforms and 4,531 cell-type-specific splicing events. Long reads uncover coordinated splicing and cell-type-specific intron retention events, which are challenging to study with short reads. Retained neuronal introns are enriched in RNA splicing regulators, showing shorter lengths, higher GC contents, and weaker 5′ splice sites. We use this dataset to explore the biological processes underlying neurological disorders, focusing on autism. In comparison with prior transcriptomic data, we find that the splicing program in autistic brains is closer to the progenitor state than differentiated neurons. Furthermore, cell-type-specific exons harbor significantly more de novo mutations in autism probands than in siblings. Overall, these results highlight the importance of cell-type-specific splicing in autism and neuronal gene regulation. |
| first_indexed | 2024-03-09T14:06:20Z |
| format | Article |
| id | doaj.art-dc72d4aca3a94f959b24712dd28855b4 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-03-09T14:06:20Z |
| publishDate | 2023-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-dc72d4aca3a94f959b24712dd28855b42023-11-30T05:06:50ZengElsevierCell Reports2211-12472023-11-014211113335Single-cell long-read sequencing in human cerebral organoids uncovers cell-type-specific and autism-associated exonsYalan Yang0Runwei Yang1Bowei Kang2Sheng Qian3Xin He4Xiaochang Zhang5Department of Human Genetics, Neuroscience Institute, The University of Chicago, Chicago, IL 60637, USADepartment of Human Genetics, Neuroscience Institute, The University of Chicago, Chicago, IL 60637, USADepartment of Human Genetics, Neuroscience Institute, The University of Chicago, Chicago, IL 60637, USADepartment of Human Genetics, Neuroscience Institute, The University of Chicago, Chicago, IL 60637, USADepartment of Human Genetics, Neuroscience Institute, The University of Chicago, Chicago, IL 60637, USA; Corresponding authorDepartment of Human Genetics, Neuroscience Institute, The University of Chicago, Chicago, IL 60637, USA; Corresponding authorSummary: Dysregulation of alternative splicing has been repeatedly associated with neurodevelopmental disorders, but the extent of cell-type-specific splicing in human neural development remains largely uncharted. Here, single-cell long-read sequencing in induced pluripotent stem cell (iPSC)-derived cerebral organoids identifies over 31,000 uncatalogued isoforms and 4,531 cell-type-specific splicing events. Long reads uncover coordinated splicing and cell-type-specific intron retention events, which are challenging to study with short reads. Retained neuronal introns are enriched in RNA splicing regulators, showing shorter lengths, higher GC contents, and weaker 5′ splice sites. We use this dataset to explore the biological processes underlying neurological disorders, focusing on autism. In comparison with prior transcriptomic data, we find that the splicing program in autistic brains is closer to the progenitor state than differentiated neurons. Furthermore, cell-type-specific exons harbor significantly more de novo mutations in autism probands than in siblings. Overall, these results highlight the importance of cell-type-specific splicing in autism and neuronal gene regulation.http://www.sciencedirect.com/science/article/pii/S2211124723013475CP: NeuroscienceCP: Molecular biology |
| spellingShingle | Yalan Yang Runwei Yang Bowei Kang Sheng Qian Xin He Xiaochang Zhang Single-cell long-read sequencing in human cerebral organoids uncovers cell-type-specific and autism-associated exons Cell Reports CP: Neuroscience CP: Molecular biology |
| title | Single-cell long-read sequencing in human cerebral organoids uncovers cell-type-specific and autism-associated exons |
| title_full | Single-cell long-read sequencing in human cerebral organoids uncovers cell-type-specific and autism-associated exons |
| title_fullStr | Single-cell long-read sequencing in human cerebral organoids uncovers cell-type-specific and autism-associated exons |
| title_full_unstemmed | Single-cell long-read sequencing in human cerebral organoids uncovers cell-type-specific and autism-associated exons |
| title_short | Single-cell long-read sequencing in human cerebral organoids uncovers cell-type-specific and autism-associated exons |
| title_sort | single cell long read sequencing in human cerebral organoids uncovers cell type specific and autism associated exons |
| topic | CP: Neuroscience CP: Molecular biology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124723013475 |
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