PMID- 26700815 OWN - NLM STAT- MEDLINE DCOM- 20160125 LR - 20240104 IS - 1476-4687 (Electronic) IS - 0028-0836 (Print) IS - 0028-0836 (Linking) VI - 529 IP - 7584 DP - 2016 Jan 7 TI - Insulator dysfunction and oncogene activation in IDH mutant gliomas. PG - 110-4 LID - 10.1038/nature16490 [doi] AB - 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. FAU - Flavahan, William A AU - Flavahan WA AD - Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA. AD - Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA. AD - Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA. FAU - Drier, Yotam AU - Drier Y AD - Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA. AD - Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA. AD - Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA. FAU - Liau, Brian B AU - Liau BB AD - Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA. AD - Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA. AD - Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA. FAU - Gillespie, Shawn M AU - Gillespie SM AD - Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA. AD - Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA. AD - Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA. FAU - Venteicher, Andrew S AU - Venteicher AS AD - Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA. AD - Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA. AD - Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA. FAU - Stemmer-Rachamimov, Anat O AU - Stemmer-Rachamimov AO AD - Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA. FAU - Suva, Mario L AU - Suva ML AD - Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA. AD - Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA. FAU - Bernstein, Bradley E AU - Bernstein BE AD - Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA. AD - Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA. AD - Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA. LA - eng SI - GEO/GSE70991 GR - DP1 CA216873/CA/NCI NIH HHS/United States GR - P50 CA165962/CA/NCI NIH HHS/United States GR - U54 HG006991/HG/NHGRI NIH HHS/United States GR - Howard Hughes Medical Institute/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20151223 PL - England TA - Nature JT - Nature JID - 0410462 RN - 0 (CCCTC-Binding Factor) RN - 0 (CTCF protein, human) RN - 0 (Cell Cycle Proteins) RN - 0 (Chromatin) RN - 0 (Chromosomal Proteins, Non-Histone) RN - 0 (Glutarates) RN - 0 (Repressor Proteins) RN - 2889-31-8 (alpha-hydroxyglutarate) RN - EC 1.1.1.41 (Isocitrate Dehydrogenase) RN - EC 1.1.1.42. (IDH1 protein, human) RN - EC 2.7.10.1 (Receptor, Platelet-Derived Growth Factor alpha) SB - IM CIN - Nature. 2016 Jan 7;529(7584):34-5. PMID: 26700812 CIN - Nat Rev Clin Oncol. 2016 Feb;13(2):64. PMID: 26787277 CIN - Trends Mol Med. 2016 Mar;22(3):185-7. PMID: 26856236 CIN - Cancer Cell. 2016 Feb 8;29(2):139-40. PMID: 26859452 CIN - Neurosurgery. 2016 Jun;78(6):N20-2. PMID: 27191813 MH - Base Sequence MH - Binding Sites MH - CCCTC-Binding Factor MH - CRISPR-Cas Systems/genetics MH - Cell Cycle Proteins/metabolism MH - Cell Proliferation/drug effects MH - Cell Transformation, Neoplastic/drug effects MH - Cells, Cultured MH - Chromatin/drug effects/genetics/metabolism MH - Chromosomal Proteins, Non-Histone/metabolism MH - CpG Islands/genetics MH - DNA Methylation/drug effects/genetics MH - Down-Regulation/drug effects MH - Enhancer Elements, Genetic/genetics MH - Epigenesis, Genetic/drug effects MH - *Gene Expression Regulation, Neoplastic/drug effects MH - Glioma/drug therapy/*enzymology/*genetics/pathology MH - Glutarates/metabolism MH - Humans MH - Insulator Elements/drug effects/*genetics MH - Isocitrate Dehydrogenase/chemistry/*genetics/metabolism MH - Mutation/*genetics MH - Oncogenes/*genetics MH - Phenotype MH - Protein Binding MH - Receptor, Platelet-Derived Growth Factor alpha/genetics MH - Repressor Proteins/metabolism MH - Up-Regulation MH - Cohesins PMC - PMC4831574 MID - NIHMS741418 COIS- The authors declare no competing interests. EDAT- 2015/12/25 06:00 MHDA- 2016/01/26 06:00 PMCR- 2016/06/23 CRDT- 2015/12/25 06:00 PHST- 2015/07/06 00:00 [received] PHST- 2015/11/26 00:00 [accepted] PHST- 2015/12/25 06:00 [entrez] PHST- 2015/12/25 06:00 [pubmed] PHST- 2016/01/26 06:00 [medline] PHST- 2016/06/23 00:00 [pmc-release] AID - nature16490 [pii] AID - 10.1038/nature16490 [doi] PST - ppublish SO - Nature. 2016 Jan 7;529(7584):110-4. doi: 10.1038/nature16490. Epub 2015 Dec 23.