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GEO help: Mouse over screen elements for information. |
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| Status |
Public on May 28, 2024 |
| Title |
High-throughput sensitive screening of small molecule modulators of microexon alternative splicing using dual Nano and Firefly luciferase reporters |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Disruption of alternative splicing frequently causes or contributes to human diseases and disorders. Consequently, there is a need for efficient and sensitive reporter assays capable of screening chemical libraries for compounds with efficacy in modulating important splicing events. Here, we describe a screening workflow employing dual Nano and Firefly luciferase alternative splicing reporters that affords highly efficient, sensitive, and linear detection of small molecule responses. Applying this system to a screen of ~95,000 small molecules, we identify compounds that selectively activate or repress a neuronal microexon network that is frequently disrupted in autism and overexpressed in neuroendocrine cancers. Remarkably, among the most potent and selective activating compounds are histone deacetylase (HDAC) inhibitors. We thus describe a high-throughput screening system for candidate splicing therapeutics, a resource of small molecule modulators of microexons, and insight into the mode of action and potential utility of HDAC inhibitors in the context of neurological disorders.
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| Overall design |
Gene expression and alternative splicing analysis of RNA-seq of mouse neuroblastoma cells treated with small-molecule compounds (single replicates or duplicates) or DMSO control
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| Contributor(s) |
Best AJ, Braunschweig U, Lim J, Farhangmehr S, Pasculescu A, Wu M, Comsa LC, Jen M, Wang J, Datti A, Wrana JL, Cordes S, Al-awar R, Han H, Blencowe BJ |
| Citation(s) |
39068192 |
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| Submission date |
Mar 30, 2023 |
| Last update date |
Aug 11, 2024 |
| Contact name |
Ulrich Braunschweig |
| Organization name |
University of Toronto
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| Department |
Donnelly Centre
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| Lab |
Benjamin J. Blencowe
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| Street address |
160 College Street
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| City |
Toronto |
| State/province |
Ontario |
| ZIP/Postal code |
M5S 3E1 |
| Country |
Canada |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (34)
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| GSM7133772 |
N2A cells, OICR.KI.2016_1_D05 |
| GSM7133773 |
N2A cells, DMSO, replicate B |
| GSM7133774 |
N2A cells, DMSO, replicate C |
| GSM7133775 |
N2A cells, BRD4884, replicate A |
| GSM7133776 |
N2A cells, BRD4884, replicate B |
| GSM7133777 |
N2A cells, BRD6688, replicate A |
| GSM7133778 |
N2A cells, BRD6688, replicate B |
| GSM7133779 |
N2A cells, CI_994, replicate A |
| GSM7133780 |
N2A cells, CI_994, replicate B |
| GSM7133781 |
N2A cells, Vorinostat_SAHA, replicate B |
| GSM7133782 |
N2A cells, Maybridge_21_O19 |
| GSM7133783 |
N2A cells, Maybridge_22_G18 |
| GSM7133784 |
N2A cells, Maybridge_98_D13 |
| GSM7133785 |
N2A cells, Maybridge_121_K16 |
| GSM7133786 |
N2A cells, Maybridge_26_F05 |
| GSM7133787 |
N2A cells, Maybridge_138_F05 |
| GSM7133788 |
N2A cells, Maybridge_109_D22 |
| GSM7133789 |
N2A cells, OICR.KI.2016_2_G19 |
| GSM7133790 |
N2A cells, OICR.KI.2016_2_O14 |
| GSM7133791 |
N2A cells, OICR.KI.2016_2_L17 |
| GSM7133792 |
N2A cells, OICR.KI.2016_2_B15 |
| GSM7133793 |
N2A cells, OICR.KI.2016_1_P14 |
| GSM7133794 |
N2A cells, Maybridge_2_M15 |
| GSM7133795 |
N2A cells, Maybridge_143_I12 |
| GSM7133796 |
N2A cells, OICR.24K.Dissimilar_40_D08 |
| GSM7133797 |
N2A cells, OICR.24K.Dissimilar_47_J19 |
| GSM7133798 |
N2A cells, OICR.24K.Dissimilar_52_B08 |
| GSM7133799 |
N2A cells, OICR.24K.Dissimilar_55_A11 |
| GSM7133800 |
N2A cells, Maybridge_67_G04 |
| GSM7133801 |
N2A cells, OICR.24K.Dissimilar_18_P14 |
| GSM7133802 |
N2A cells, Lopac_1_G11 |
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| Relations |
| BioProject |
PRJNA950424 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE228599_AltSplicing.tab.gz |
17.9 Mb |
(ftp)(http) |
TAB |
| GSE228599_Expression.tab.gz |
6.7 Mb |
(ftp)(http) |
TAB |
| GSE228599_vast-tools.AltSplicing.tab.gz |
76.7 Mb |
(ftp)(http) |
TAB |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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