IDH mutation impairs histone demethylation and results in a block to cell differentiation

Chao Lu, Patrick S. Ward, Gurpreet S. Kapoor, Dan Rohle, Sevin Turcan, Omar Abdel-Wahab, Christopher R. Edwards, Raya Khanin, Maria Figueroa, Ari Melnick, Kathryn E. Wellen, Donald M. Oĝrourke, Shelley L. Berger, Timothy A. Chan, Ross L. Levine, Ingo K. Mellinghoff, Craig B. Thompson

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)474-478
Number of pages5
JournalNature
Volume483
Issue number7390
DOIs
StatePublished - Mar 22 2012
Externally publishedYes

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Histones
Cell Differentiation
Methylation
Mutation
Histone Code
Glioma
DNA Methylation
Adipocytes
Stem Cells
Isocitrate Dehydrogenase
Chondrosarcoma
RNA Interference
Transcriptome
Acute Myeloid Leukemia
Astrocytes
Genes
Transfection
alpha-hydroxyglutarate
Neoplasms

ASJC Scopus subject areas

  • Medicine(all)
  • General

Cite this

Lu, C., Ward, P. S., Kapoor, G. S., Rohle, D., Turcan, S., Abdel-Wahab, O., ... Thompson, C. B. (2012). IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature, 483(7390), 474-478. https://doi.org/10.1038/nature10860

IDH mutation impairs histone demethylation and results in a block to cell differentiation. / Lu, Chao; Ward, Patrick S.; Kapoor, Gurpreet S.; Rohle, Dan; Turcan, Sevin; Abdel-Wahab, Omar; Edwards, Christopher R.; Khanin, Raya; Figueroa, Maria; Melnick, Ari; Wellen, Kathryn E.; Oĝrourke, Donald M.; Berger, Shelley L.; Chan, Timothy A.; Levine, Ross L.; Mellinghoff, Ingo K.; Thompson, Craig B.

In: Nature, Vol. 483, No. 7390, 22.03.2012, p. 474-478.

Research output: Contribution to journalArticle

Lu, C, Ward, PS, Kapoor, GS, Rohle, D, Turcan, S, Abdel-Wahab, O, Edwards, CR, Khanin, R, Figueroa, M, Melnick, A, Wellen, KE, Oĝrourke, DM, Berger, SL, Chan, TA, Levine, RL, Mellinghoff, IK & Thompson, CB 2012, 'IDH mutation impairs histone demethylation and results in a block to cell differentiation', Nature, vol. 483, no. 7390, pp. 474-478. https://doi.org/10.1038/nature10860
Lu C, Ward PS, Kapoor GS, Rohle D, Turcan S, Abdel-Wahab O et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature. 2012 Mar 22;483(7390):474-478. https://doi.org/10.1038/nature10860
Lu, Chao ; Ward, Patrick S. ; Kapoor, Gurpreet S. ; Rohle, Dan ; Turcan, Sevin ; Abdel-Wahab, Omar ; Edwards, Christopher R. ; Khanin, Raya ; Figueroa, Maria ; Melnick, Ari ; Wellen, Kathryn E. ; Oĝrourke, Donald M. ; Berger, Shelley L. ; Chan, Timothy A. ; Levine, Ross L. ; Mellinghoff, Ingo K. ; Thompson, Craig B. / IDH mutation impairs histone demethylation and results in a block to cell differentiation. In: Nature. 2012 ; Vol. 483, No. 7390. pp. 474-478.
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AU - Abdel-Wahab, Omar

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