Publication Date:
2015-12-25
Description:
Gain-of-function IDH mutations are initiating events that define major clinical and prognostic classes of gliomas. Mutant IDH protein produces a new onco-metabolite, 2-hydroxyglutarate, which interferes with iron-dependent hydroxylases, including the TET family of 5'-methylcytosine hydroxylases. TET enzymes catalyse a key step in the removal of DNA methylation. IDH mutant gliomas thus manifest a CpG island methylator phenotype (G-CIMP), although the functional importance of this altered epigenetic state remains unclear. Here we show that human IDH mutant gliomas exhibit hypermethylation at cohesin and CCCTC-binding factor (CTCF)-binding sites, compromising binding of this methylation-sensitive insulator protein. Reduced CTCF binding is associated with 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 interact aberrantly with the receptor tyrosine kinase gene PDGFRA, a prominent glioma oncogene. Treatment of IDH mutant gliomaspheres with a demethylating agent partially restores insulator function and downregulates PDGFRA. Conversely, CRISPR-mediated disruption of the CTCF motif in IDH wild-type gliomaspheres upregulates PDGFRA and increases proliferation. Our study suggests that IDH mutations promote gliomagenesis by disrupting chromosomal topology and allowing aberrant regulatory interactions that induce oncogene expression.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Flavahan, William A -- Drier, Yotam -- Liau, Brian B -- Gillespie, Shawn M -- Venteicher, Andrew S -- Stemmer-Rachamimov, Anat O -- Suva, Mario L -- Bernstein, Bradley E -- Howard Hughes Medical Institute/ -- England -- Nature. 2016 Jan 7;529(7584):110-4. doi: 10.1038/nature16490. Epub 2015 Dec 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA. ; Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA. ; Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA. ; Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26700815" target="_blank"〉PubMed〈/a〉
Keywords:
Base Sequence
;
Binding Sites
;
CRISPR-Cas Systems/genetics
;
Cell Cycle Proteins/metabolism
;
Cell Proliferation/drug effects
;
Cell Transformation, Neoplastic/drug effects
;
Cells, Cultured
;
Chromatin/drug effects/genetics/metabolism
;
Chromosomal Proteins, Non-Histone/metabolism
;
CpG Islands/genetics
;
DNA Methylation/drug effects/genetics
;
Down-Regulation/drug effects
;
Enhancer Elements, Genetic/genetics
;
Epigenesis, Genetic/drug effects
;
*Gene Expression Regulation, Neoplastic/drug effects
;
Glioma/drug therapy/*enzymology/*genetics/pathology
;
Glutarates/metabolism
;
Humans
;
Insulator Elements/drug effects/*genetics
;
Isocitrate Dehydrogenase/chemistry/*genetics/metabolism
;
Mutation/*genetics
;
Oncogenes/*genetics
;
Phenotype
;
Protein Binding
;
Receptor, Platelet-Derived Growth Factor alpha/genetics
;
Repressor Proteins/metabolism
;
Up-Regulation
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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