DOT1L Inhibits SIRT1 and SUV39H1-Mediated H3K9 Modification to Maintain Gene Expression (array)

Methylation of histone 3 on lysine 79 (H3K79) is broadly associated with active gene expression in eukaryotes, and the H3K79 methyltransferase DOT1L is indispensable for specific leukemia subtypes like those with MLL-translocations. We found that suppression of the histone deacetylase SIRT1 rescued MLL-AF9 leukemia cells from their dependence on DOT1L. We show that upon DOT1L inhibition, SIRT1 is required for the acquisition of a repressive chromatin state consistent with facultative heterochromatin around MLL-AF9 target genes in leukemia and other genes possess an H3K79me2(hi), H3K9ac(hi), H3K9me2(low) histone modification profile in normal hematopoietic stem and progenitor cells. Examination of gene expression dynamics with and without drug treatment and RNA interference.