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LSD1-Mediated Demethylation of Histone H3 Lysine 4 Triggers Myc-Induced Transcription

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LSD1-Mediated Demethylation of Histone H3 Lysine 4 Triggers Myc-Induced Transcription Oncogene (2010) 29, 3691–3702 & 2010 Macmillan Publishers Limited All rights reserved 0950-9232/10 www.nature.com/onc ORIGINAL ARTICLE LSD1-mediated demethylation of histone H3 lysine 4 triggers Myc-induced transcription S Amente1,2, A Bertoni3, A Morano3, L Lania1,2, EV Avvedimento2,3 and B Majello1 1Department of Structural and Functional Biology, University of Naples ‘Federico II’, Naples, Italy; 2Naples Oncogenomic Center (CEINGE), Naples, Italy and 3Department of Biology, Cellular and Molecular Pathology, ‘L. Califano’ University of Naples ‘Federico II’, Naples, Italy Myc is a transcription factor that significantly contributes methylation (Kouzarides, 2007). Furthermore, lysine to cancer progression by modulating the expression of residues can be mono-, di- or trimethylated, and it has important genes through binding to a DNA sequence, been suggested that each methylation state represents a CACGTG, called E-box. We find that on Myc binding to specific epigenetic marker with a precise biological chromatin, the lysine-demethylating enzyme, LSD1, meaning in transcription (Shi, 2007; Cloos et al., 2008; triggers a transient demethylation of lysine 4 in the Kirmizis et al., 2009). histone H3. In addition, we demonstrate that Myc binds The c-myc proto-oncogene is an essential activator of and recruits LSD1 to the E-box chromatin and the cell proliferation and one of the genes most commonly formation of this complex is stimulated by cAMP-PKA. deregulated in cancer (Cowling and Cole, 2006; Eilers Demethylation by LSD1 produces H2O2, which locally and Eisenman, 2008; Meyer and Penn, 2008). The Myc oxidizes guanine and induces the recruitment of 8-oxo- protein binds to a multitude of sites in the human guanine–DNA glycosylase (OGG1) and of the nuclease genome; it has been estimated that 15% of all promoter Ape1 on the E-box chromatin. Inhibition of oxidation regions in the human genome are potentially Myc- or silencing of LSD1, OGG1 or Ape1 significantly binding targets (Fernandez et al., 2003; Guccione et al., reduce transcription and inhibit mRNA accumulation of 2006; Zeller et al., 2006). Once bound to its targets, Myc Myc-target genes. Collectively, these data highlight the introduces changes on chromatin. It is known that Myc role of transient LSD1-mediated demethylation of H3K4 can interact with several histone modifiers resulting in leading to local DNA oxidation as driving force in the hyperacetylation of histones and transcriptional activa- assembly of the Myc-induced transcription initiation tion (McMahon et al., 2000; Frank et al., 2001; Frank complex. et al., 2003; Vervoorts et al., 2003; Secombe et al., 2007). Oncogene (2010) 29, 3691–3702; doi:10.1038/onc.2010.120; Despite the large bulk of information on Myc-induced published online 26 April 2010 histone acetylation, little is known about the effects of Myc on histone methylation (Secombe et al., 2007). Keywords: Myc; LSD1; transcription; histone; Large-scale or quantitative chromatin immunoprecipi- methylation; oxidative burst tation (qChIP) with probes specific for various histone post-transcriptional modifications shows that Myc- binding targets can be classified in specific groups, characterized by different histones marks (Guccione Introduction et al., 2006; Martinato et al., 2008). To find the link between histone modifications The basic building blocks of chromatin are the nucleo- induced by Myc and transcription, we have examined somes composed of DNA wrapped around a histone the consequences of specific changes of methylation octamer. The N-terminal tails of histones are subjected marks in the histone H3 tail, by using a conditional Myc to different post-translational modifications: phospho- expression system. We focused our attention on two rylation, ubiquitination, acetylation and methylation, Myc-target genes, Ncl (nucleolin) and Cad (carbamoyl- which affect chromatin structure and transcription transferase-dihydroorotase), selected from high-affinity (Berger, 2007; Kouzarides, 2007). It has been shown E-box human Myc-regulated promoters with high levels that transcriptional activation is linked to H3K4, of H3K4 methylation (Guccione et al., 2006; Martinato H3K36 and H3K79 methylation, whereas transcrip- et al., 2008). tional repression is associated with H3K9 and H3K27 Our data indicate that Myc binds to the E-boxes sequences of Ncl and Cad and triggers a transient Correspondence: Dr B Majello, Department of Structural and demethylation of H3K4me2 before significant changes Functional Biology, University of Naples Federico II, Via Cinthia, in local histone acetylation become apparent. We find Naples 80126, Italy. E-mail: [email protected] that Myc binds and facilitates the recruitment of the Received 5 November 2009; revised 8 March 2010; accepted 16 March lysine-specific demethylase, LSD1 (Shi et al., 2004; Shi, 2010; published online 26 April 2010 2007), to the E-box chromatin. Both the binding and LSD1-induced H3 demethylation drives Myc transactivation S Amente et al 3692 recruitment of LSD1 are stimulated by cAMP-PKA or present in the absence of Myc on the TSS (0). As soon as serum. LSD1 is a flavin adenine dinucleotide (FAD)- Myc binds to the E-box, RNAPII moves from the 0 containing enzyme, which generates H2O2 during the promoter site and progressively accumulates at 30 on demethylation process (Forneris et al., 2005; Anand and the CRs (compare the signal at 0 and 30 on the TSS and Marmorstein, 2007; Lan et al., 2008). Oxidation of CR). At 600 after Myc activation, RNAPII is again guanine by H2O2 recruits components of the base recruited on the TSS. Concomitantly, after 1 h of Myc excision repair system, the 8-oxoguanine–DNA glyco- induction, stable Ncl and Cad mRNA begins to sylase, OGG1, and the Ape1 lyase (Sidorenko et al, accumulate (Supplementary Figure 2c). Comparing the 2007; Tell et al., 2008) on the E-box and promoter relative site occupancy of RNAPII on TSS and CR, we chromatin regions of Myc-target genes. According to can speculatively suggest a transcription cycle induced these results, inhibition of oxidation or silencing of by Myc with a period of 45–600. Acetylated histone H4 LSD1, OGG1 or Ape1 significantly affects Myc-induced steadily accumulates on the TSS and CR of both genes, transcription. peaking 2400 after Myc activation. Collectively, these data suggest a mechanism for the We have analyzed the methylation marks on these initiation of transcription induced by Myc and highlight regions following Myc binding, focusing our attention the role of LSD1-mediated demethylation of histone on lysines 4 and 9 of histone H3. Figure 2 (Ncl gene) H3K4 as a driving force in the assembly of the shows that H3K4me3 and H3K9me2 levels remain transcription initiation complex of Myc targets. stable except for a slight demethylation of H3K4me3 on the E-box chromatin after Myc binding (0–30). H3K4me2, on the other end, undergoes demethylation on the TTS and E-box on Myc binding. H3K4me2 levels Results return to the basal level 4 h after Myc activation. On the US chromatin, H3K4me2 levels decrease at 300 and Myc induces H3K4 demethylation cycles on the E-box rapidly return to the basal level at 600. Similar changes in chromatin H3K4me2 and me3 are detectable on the chromatin of Myc binds the E-box regions in the genome containing Cad gene (Supplementary Figure 1). the hexanucleotide 50-CANNTG-30 (Cowling and Cole, The description of the changes in H3K4 methylation, 2006). The chromatin context, the so-called ‘histone following Myc binding on the E-box chromatin, code’, determines the binding and possibly the trans- suggests that Myc-induced transcription is accompanied criptional outcome. However, notwithstanding extensive by cycles of methylation and demethylation of lysine 4 analysis of chromatin regions activated or repressed by in histone H3, before the robust burst of H4 acetylation. Myc, up to now there is no clear definition of the These data confirm and extends the notion that H3K4 chromatin domains recognized and modified by the methylated chromatin characterizes high-affinity Myc protein. promoters (Guccione et al., 2006). qChIP with various probes targeting histone post- transcriptional modifications indicates that Myc-respon- sive regions are characterized by specific histone marks. Myc recruits LSD1 on the chromatin and triggers H3K4 High-affinity Myc-binding sites are marked by methyla- demethylation tion of lysine 4 in the histone H3 tail, a signature of The results shown in Figure 1 indicate that, on Myc transcriptional activation (Guccione et al., 2006; Zeller binding, H3K4me2 is subjected to demethylation. As et al., 2006; Martinato et al., 2008). We have focused H3K4me2 is a substrate of the lysine-specific demethy- our attention on two prototypic Myc-target genes, Ncl lase, LSD1 (Forneris et al., 2008), we have investigated and Cad, showing high levels of H3K4 methylation the recruitment of this enzyme on Ncl and Cad and we have analyzed the methylation changes on Myc chromatin. Figure 2 and Supplementary Figure 1 show expression. that LSD1 is transiently recruited on Ncl and Cad We have used the Rat-MycER cell line (Littlewood sequences shortly after Myc activation. Although et al., 1995; Gargano et al., 2007) in which the MycER Myc binding increases over time essentially on the protein is activated on treatment of the cells with E-box, LSD1 binding is observed predominantly on tamoxifen (OHT). The cells are serum starved for 2 days the E-box and TSS regions but it is also seen on the and then are treated with OHT and serum. US sequence and CRs. The recruitment of LSD1 to To assess Myc and RNAPII occupancy on Ncl and the chromatin of these Myc-induced promoters is an Cad genomic sites in a precise temporal frame after Myc early and transient event, which overlaps to the wave activation, we carried out qChIP analysis on upstream of H3K4me2 demethylation. This result suggests a (US), transcription start site (TSS), E-box and coding functional relation between LDS1 recruitment and regions (CRs) of Ncl and Cad genes at 0, 30, 60 and 2400 H3K4me2 demethylation.
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