About this item:

710 Views | 1,005 Downloads

Author Notes:

Corresponding authors E-mail hai.yan@dm.duke.edu E-mail pvertin@emory.edu

CGD and BGB contributed equally to this work.

We thank members of the Yan and Vertino Labs for technical help and helpful discussions.

We thank I. Spasojevic, P. Fan, and the DUCC Clinical Pharmacology Lab for quantitative analysis of D-2-HG; K. Abramson and the Duke CHG Molecular Genetics Core for their assistance with the Methylation Array Studies; and the Duke Microarray Core Facility for their assistance with the microarray studies.

Subject:

Research Funding:

This project was supported by American Cancer Society Research Scholar Award RSG-10-126-01-CCE, The Pediatric Brain Tumor Foundation Institute Grant, The Southeastern Brain Tumor Foundation Grant, and NCI Grant 5R01-CA140316 (to H.Y.), NCI Grants 2R01-CA077337 and 5R01-CA132065 (to P.M.V.), as well as by the following NIH grants: NINDS Grant 5P50 NS20023 (to D.D.B.), NCI SPORE Grant 5P50 CA108786 (to D.D.B.), and NCI Merit Award R37 CA 011898 (to D.D.B.).

H.Y. received a research grant and consulting fee from Sanofi-aventis.

A heterozygous IDH1R132H/WT mutation induces genome-wide alterations in DNA methylation

Tools:

Journal Title:

Genome Research

Volume:

Number 22

Publisher:

, Pages 2339-2355

Type of Work:

Article | Final Publisher PDF

Abstract:

Monoallelic point mutations of the NADP+-dependent isocitrate dehydrogenases IDH1 and IDH2 occur frequently in gliomas, acute myeloid leukemias, and chondromas, and display robust association with specific DNA hypermethylation signatures. Here we show that heterozygous expression of the IDH1R132H allele is sufficient to induce the genome-wide alterations in DNA methylation characteristic of these tumors. Using a gene-targeting approach, we knocked-in a single copy of the most frequently observed IDH1 mutation, R132H, into a human cancer cell line and profiled changes in DNA methylation at over 27,000 CpG dinucleotides relative to wild-type parental cells. We find that IDH1R132H/WT mutation induces widespread alterations in DNA methylation, including hypermethylation of 2010 and hypomethylation of 842 CpG loci. We demonstrate that many of these alterations are consistent with those observed in IDH1-mutant and G-CIMP+ primary gliomas and can segregate IDH wild-type and mutated tumors as well as those exhibiting the G-CIMP phenotype in unsupervised analysis of two primary glioma cohorts. Further, we show that the direction of IDH1R132H/WT-mediated DNA methylation change is largely dependent upon preexisting DNA methylation levels, resulting in depletion of moderately methylated loci. Additionally, whereas the levels of multiple histone H3 and H4 methylation modifications were globally increased, consistent with broad inhibition of histone demethylation, hypermethylation at H3K9 in particular accompanied locus-specific DNA hypermethylation at several genes down-regulated in IDH1R132H/WT knock-in cells. These data provide insight on epigenetic alterations induced by IDH1 mutations and support a causal role for IDH1R132H/WT mutants in driving epigenetic instability in human cancer cells.

Copyright information:

© 2012, Published by Cold Spring Harbor Laboratory Press

This is an Open Access work distributed under the terms of the Creative Commons Attribution-Noncommercial 3.0 Unported License (http://creativecommons.org/licenses/by-nc/3.0/).

Creative Commons License

Export to EndNote