新たな核内ビタミンA受容体転写共役活性化因子(ヒストンメチル化酵素)による遺伝子活性化の分子機構

概要

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Dynamic exchange of post-translational modification of histone tails is a crucial step for cellular differentiation. Lineage-specific histone modifying enzymes have been considered to epigenetically convert to cell-specific chromatin structure and transcriptional outcome. Although multiple histone lysine methyltransferases (HKMTs) are involved in transcriptional memory, the molecular basis how they establish epigenetic methylmarks is not clear. Here, we report that nuclear O-Glycosylation of MLL5 triggers its HKMT activity on histone H3 lysine 4 (H3K4) and this defines the ability of promyelocytes to differentiate into granulocytes by retinoic acid (RA). We have first identified MLL5, SET domain-containing putative HKMT, as a ligand-dependent co-activator of nuclear RA receptors (RARs) in promyelocytes. HKMT-active MLL5 complex has been found to contain O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT). OGT subunit functionally activated HKMT activity of MLL5 through O-GlcNAc modification on threonine 440 within its catalytic SET domain. Retroviral expression of O-GlcNAc-deficient MLL5 mutant dramatically impaired both RA-induced and O-GlcNAc-stimulated differentiation of promyelocytes. Hence, these findings provide first evidence that nuclear O-glycosylation in promyelocytes modulates the cellular sensitivity to RA for inducing epigenetic exchange of H3K4 methylation by MLL5 to define granulocytic commitment.
2009-08-25