Sep 8, 2009

Impaired recruitment of the histone methyltransferase DOT1L contributes to the incomplete reactivation of tumor suppressor genes upon DNA demethylation

Oncogene
F V JacintoM Esteller

Abstract

Understanding the mechanisms that link changes in DNA methylation with histone modifications is particularly relevant in the case of tumor suppressor genes that undergo transcriptional silencing in cancer cells in association with promoter CpG island hypermethylation. In this study, we show that two histone lysine methylation marks associated with active transcription, dimethylation of H3K79 (H3K79me2) and trimethylation of H3K4 (H3K4me3), are present in all the unmethylated promoters analysed, and both of them are lost when these promoters become hypermethylated. Most importantly, pharmacological and genetic interventions that cause DNA demethylation and partial recovery of gene transcription, result in the restoration of H3K4me3, but not of H3K79me2. We also show that DOT1L, the major H3K79 histone methyltransferase, is no longer recruited to the promoters that are demethylated after 5-aza-deoxycytidine treatment or genetic deletion of DNA methyltransferases. Knock-down and transfection experiments for DOT1L show that this enzyme has a direct role in maintaining the euchromatic and active status of these genes when unmethylated. These findings suggest that DNA demethylating interventions alone are not able to restore a comple...Continue Reading

  • References26
  • Citations16

Citations

Mentioned in this Paper

Gene Expression Regulation, Neoplastic
Tumor Suppressor Genes
Transfection
Metastasis Suppressor Genes
Transcription, Genetic
Changes in DNA Methylation
Gene Deletion Abnormality
DNA Methylation
DOT1L gene
Histone methyltransferase

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