|
| Status |
Public on Dec 23, 2015 |
| Title |
Insulator dysfunction and oncogene activation in IDH mutant gliomas |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
|
| Summary |
Gain-of-function IDH mutations define major clinical and prognostic classes of gliomas. Mutant IDH protein produces a novel onco-metabolite, 2-hydroxyglutarate (2-HG), that interferes with iron-dependent hydroxylase enzymes, including the TET family of 5'-methylcytosine hydroxylases. TET enzymes are critical for the dynamic regulation of DNA methylation. IDH mutant gliomas thus manifest a CpG island methylator phenotype (G-CIMP), though the functional significance of this altered epigenetic state remains unclear. Here we show that IDH1 mutant gliomas exhibit hyper-methylation at CTCF binding sites, leading to reduced binding of this methylation-sensitive insulator protein. Loss of CTCF binding is associated with a loss of insulation between topological domains and aberrant gene activation. We specifically demonstrate that loss of CTCF at a domain boundary permits a constitutive enhancer to aberrantly interact with the receptor tyrosine kinase gene PDGFRA, a prominent glioma oncogene. Treatment of IDH mutant gliomaspheres with demethylating agent partially restores insulator function and reduces PDGFRA expression. Conversely, CRISPR-mediated disruption of the CTCF binding sequence in IDH wildtype gliomaspheres induces PDGFRA expression and increases proliferation. Our study suggests that IDH mutations promote gliomagenesis by disrupting chromosomal topology and allowing aberrant regulatory interactions that induce oncogene expression.
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| |
|
| Overall design |
CTCF occupancy characterization and histone H3K27 acetylation profiling in IDH1 mutant and wild-type glioma patient specimens and culture models.
ChIP-seq raw data is to be made available through dbGaP (controlled access) due to patient privacy concerns.
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| |
|
| Contributor(s) |
Flavahan WA, Drier Y, Bernstein BE |
| Citation(s) |
26700815 |
| Submission date |
Jul 16, 2015 |
| Last update date |
Mar 27, 2019 |
| Contact name |
Yotam Drier |
| E-mail(s) |
yotam.drier@mail.huji.ac.il
|
| Organization name |
The Hebrew University of Jerusalem
|
| Department |
Immunology and Cancer Research
|
| Lab |
Drier
|
| Street address |
Faculty of Medicine, The Hebrew University, Ein Kerem
|
| City |
Jerusalem |
| State/province |
Israel |
| ZIP/Postal code |
9112102 |
| Country |
Israel |
| |
|
| Platforms (3) |
| GPL15520 |
Illumina MiSeq (Homo sapiens) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
|
| Samples (33)
|
|
| Relations |
| BioProject |
PRJNA290069 |
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