LSD1-mediated demethylation of histone H3 lysine 4 triggers Myc-induced transcription.
Myc is a transcription factor that significantly contributes to cancer progression by modulating the expression of important genes through binding to a DNA sequence, CACGTG, called E-box. We find that on Myc binding to chromatin, the lysine-demethylating enzyme, LSD1, triggers a transient demethylation of lysine 4 in the histone H3. In addition, we demonstrate that Myc binds and recruits LSD1 to the E-box chromatin and the formation of this complex is stimulated by cAMP-PKA. Demethylation by LSD1 produces H(2)O(2), which locally oxidizes guanine and induces the recruitment of 8-oxoguanine-DNA glycosylase (OGG1) and of the nuclease Ape1 on the E-box chromatin. Inhibition of oxidation or silencing of LSD1, OGG1 or Ape1 significantly reduce transcription and inhibit mRNA accumulation of Myc-target genes. Collectively, these data highlight the role of transient LSD1-mediated demethylation of H3K4 leading to local DNA oxidation as driving force in the assembly of the Myc-induced transcription initiation complex.
Amente
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Department of Structural and Functional Biology, University of Naples 'Federico II', Naples, Italy.
Bertoni
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A
Morano
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Lania
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L
Avvedimento
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EV
Majello
B
B
D000818:Animals; D002460:Cell Line; D002843:Chromatin / Q000235:genetics; D004247:DNA / Q000378:metabolism; D045643:DNA Repair Enzymes / Q000378:metabolism; D024721:E-Box Elements; D056466:Histone Demethylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism*; D008745:Methylation; D008934:Mitogens / Q000494:pharmacology; D010084:Oxidation-Reduction; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D051381:Rats; D014158:Transcription, Genetic / Q000187:drug effects
D002843:Chromatin; D006657:Histones; D008934:Mitogens; D016271:Proto-Oncogene Proteins c-myc; D004247:DNA; D056466:Histone Demethylases; D045643:DNA Repair Enzymes; D008239:Lysine