TitleIDH mutation impairs histone demethylation and results in a block to cell differentiation.
Publication TypeJournal Article
Year of Publication2012
AuthorsLu, Chao, Ward Patrick S., Kapoor Gurpreet S., Rohle Dan, Turcan Sevin, Abdel-Wahab Omar, Edwards Christopher R., Khanin Raya, Figueroa Maria E., Melnick Ari, Wellen Kathryn E., O'Rourke Donald M., Berger Shelley L., Chan Timothy A., Levine Ross L., Mellinghoff Ingo K., and Thompson Craig B.
Date Published2012 Feb 15
Keywords3T3-L1 Cells, Adipocytes, Animals, Astrocytes, Cell Differentiation, Cell Line, Tumor, Cell Lineage, DNA Methylation, Enzyme Induction, Gene Expression Regulation, Glioma, Glutarates, HEK293 Cells, Histones, Humans, Isocitrate Dehydrogenase, Jumonji Domain-Containing Histone Demethylases, Methylation, Mice, Mutation, Neural Stem Cells, Promoter Regions, Genetic

<p>Recurrent mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 have been identified in gliomas, acute myeloid leukaemias (AML) and chondrosarcomas, and share a novel enzymatic property of producing 2-hydroxyglutarate (2HG) from α-ketoglutarate. Here we report that 2HG-producing IDH mutants can prevent the histone demethylation that is required for lineage-specific progenitor cells to differentiate into terminally differentiated cells. In tumour samples from glioma patients, IDH mutations were associated with a distinct gene expression profile enriched for genes expressed in neural progenitor cells, and this was associated with increased histone methylation. To test whether the ability of IDH mutants to promote histone methylation contributes to a block in cell differentiation in non-transformed cells, we tested the effect of neomorphic IDH mutants on adipocyte differentiation in vitro. Introduction of either mutant IDH or cell-permeable 2HG was associated with repression of the inducible expression of lineage-specific differentiation genes and a block to differentiation. This correlated with a significant increase in repressive histone methylation marks without observable changes in promoter DNA methylation. Gliomas were found to have elevated levels of similar histone repressive marks. Stable transfection of a 2HG-producing mutant IDH into immortalized astrocytes resulted in progressive accumulation of histone methylation. Of the marks examined, increased H3K9 methylation reproducibly preceded a rise in DNA methylation as cells were passaged in culture. Furthermore, we found that the 2HG-inhibitable H3K9 demethylase KDM4C was induced during adipocyte differentiation, and that RNA-interference suppression of KDM4C was sufficient to block differentiation. Together these data demonstrate that 2HG can inhibit histone demethylation and that inhibition of histone demethylation can be sufficient to block the differentiation of non-transformed cells.</p>

Alternate JournalNature
PubMed ID22343901
PubMed Central IDPMC3478770
Grant ListU54 CA143798 / CA / NCI NIH HHS / United States
/ HHMI / Howard Hughes Medical Institute / United States
R01 CA105463 / CA / NCI NIH HHS / United States
R01 CA078831 / CA / NCI NIH HHS / United States
U54CA143798 / CA / NCI NIH HHS / United States