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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Jan 23, 2020 |
| Title |
A suite of haploid genetic screens identifies SPRING as a novel determinant of SREBP signaling and cholesterol metabolism |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
The sterol-regulatory element binding protein (SREBP) transcription factors are central transcriptional regulators of sterol- and fatty acid metabolism. Using a suite of human haploid genetic screens, we identify the SREBP Regulating Gene (SPRING; C12ORF49) as a novel regulator of this pathway. SPRING is a glycosylated Golgi-resident membrane protein. Genetic ablation of SPRING in human Hap1 cells, murine Hepa1-6 hepatoma cells, and in primary murine hepatocytes leads to a marked reduction in SREBP signaling. In mice, deletion of Spring results in embryonic lethality. However, we show that adenoviral-mediated silencing of hepatic Spring expression also attenuates the SREBP response. Mechanistically, we demonstrate that attenuated SREBP signaling in SPRINGKO cells is a result of reduced SREBP cleavage-activating protein (SCAP) and its mislocalization. Whereas in control cells SCAP cycles between the ER and the Golgi in a sterol-dependent manner, in SPRINGKO cells SCAP is trapped in the Golgi irrespective of the cellular sterol status. Consistent with limited functional SCAP in SPRINGKO cells, reintroducing SCAP restores SREBP-dependent signaling, cholesterol biosynthesis, and lipoprotein uptake. Consistent with SREBP signaling being required for cell growth and proliferation, a wide range of human tumor cell lines display dependency on SPRING expression. In conclusion, we identify SPRING as a previously unrecognized determinant of the SREBP pathway that is essential for proper SCAP function.
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| Overall design |
Identification of a gene, SPRING (C12ORF49), as a novel regulator of the SREBP pathway and cholesterol homeostasis
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| Contributor(s) |
Zelcer N, Brummelkamp T |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
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| Submission date |
Jan 13, 2020 |
| Last update date |
Jan 23, 2020 |
| Contact name |
Noam Zelcer |
| Organization name |
AUMC
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| Department |
Medical Biochemistry
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| Street address |
Meibergdreef 9
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| City |
Amsterdam |
| ZIP/Postal code |
1105AZ |
| Country |
Netherlands |
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| Platforms (1) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
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| Samples (10)
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| Relations |
| BioProject |
PRJNA600886 |
| SRA |
SRP241720 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE143530_readcounts.txt.gz |
1.3 Mb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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