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| Status |
Public on May 01, 2023 |
| Title |
Single Copy Loss of Tet1 disrupts neural stem cell differentiation and enhances GBM aggressiveness |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Glioblastoma (GBM) is a highly aggressive brain tumor, characterized by poorly differentiated cells that drive disease growth and relapse. In contrast to normal neural stem cells (NSCs) which show a highly orderly process of differentiation, GBM precursors exhibit differentiation failure. In order to identify new mechanisms involved in neuronal differentiation that may have bearing on understanding GBM, we performed an unbiased phenotypic screen, utilizing a library of mouse embryonic stem cell (mESC) clones carrying 1307 unique variable length haplodeletions (altogether covering 25% of the mouse genome). We identified a series of haplodeletions that conferred failed neuronal differentiation following neural lineage specification. Several hit clones contained a deletion on mouse chromosome 10, synteneic to human chromosome 10q, and included the Tet1 gene. Loss of a single allele of Tet1 was sufficient to confer the failed neuronal differentiation on mouse neural precursors by allowing stem cell programs to override early commitment steps leading to full reversion back to a stem cell state. By deleting TET1 in human GBM precursors, we show that loss of one allele of TET1 is sufficient to cause increased self renewal, decreased differentiation, and increased tumorigenicity, demonstrating TET1 to be a key target, along with PTEN, on 10q. Reduced TET1 dosage leads to global DNA hypermethylation and increased sensitivity to DNA methylation inhibitors, suggesting their application in a subset of GBMs.
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| Overall design |
Human primary glioblastoma cells with a crispr-induced loss of function deletion in one or both copies of TET1 are compared to TET1 wildtype cells of matched genetic background
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| Contributor(s) |
Coutinho FJ, Dirks PB |
| Citation missing |
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| |
| Submission date |
Aug 01, 2017 |
| Last update date |
May 01, 2023 |
| Contact name |
Fiona J Coutinho |
| E-mail(s) |
fiona.coutinho@sickkids.ca
|
| Organization name |
The Hospital for Sick Children
|
| Department |
Developmental and Stem Cell Biology
|
| Lab |
Dr. Peter Dirks
|
| Street address |
686 Bay Street, PGCRL 16-9801
|
| City |
Toronto |
| State/province |
ON |
| ZIP/Postal code |
M5G 0A4 |
| Country |
Canada |
| |
|
| Platforms (1) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
|
| Samples (9)
|
| GSM2728744 |
TET1 heterozygous loss of function mutant replicate 1 |
| GSM2728745 |
TET1 heterozygous loss of function mutant replicate 2 |
| GSM2728746 |
TET1 heterozygous loss of function mutant replicate 3 |
| GSM2728747 |
TET1 homozygous loss of function mutant replicate 1 |
| GSM2728748 |
TET1 homozygous loss of function mutant replicate 2 |
| GSM2728749 |
TET1 homozygous loss of function mutant replicate 3 |
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| Relations |
| BioProject |
PRJNA396764 |
| SRA |
SRP114556 |
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