a role for methyl-cpg binding domain protein 2 in the modulation of the estrogen response of ps2tff1 genemethyl-cpg绑定的作用域蛋白2在调制ps2tff1雌激素反应的基因.pdfVIP

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a role for methyl-cpg binding domain protein 2 in the modulation of the estrogen response of ps2tff1 genemethyl-cpg绑定的作用域蛋白2在调制ps2tff1雌激素反应的基因.pdf

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a role for methyl-cpg binding domain protein 2 in the modulation of the estrogen response of ps2tff1 genemethyl-cpg绑定的作用域蛋白2在调制ps2tff1雌激素反应的基因

A Role for Methyl-CpG Binding Domain Protein 2 in the Modulation of the Estrogen Response of pS2/TFF1 Gene 1 2 2 1 Amandine Chatagnon , Esteban Ballestar , Manel Esteller , Robert Dante * 1 INSERM, U590, Lyon, France, 2 Cancer Epigenetics and Biology Programme (PEBC), Catalan Institute of Oncology (ICO-IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain Abstract Background: In human Estrogen Receptor a (ERa)-positive breast cancers, 5 9 end dense methylation of the estrogen- regulated pS2/TFF1 gene correlates with its transcriptional inhibition. However, in some ERa-rich biopsies, pS2 expression is observed despite the methylation of its TATA-box region. Herein, we investigated the methylation-dependent mechanism of pS2 regulation. Methodology/Principal Findings: We observed interplay between Methyl-CpG Binding Domain protein 2 (MBD2) transcriptional repressor and ERa transactivator: (i) the pS2 gene is poised for transcription upon demethylation limited to the enhancer region containing the estrogen responsive element (ERE); (ii) MBD2-binding sites overlapped with the methylation status of the pS2 59 end; (iii) MBD2 depletion elevated pS2 expression and ectopic expression of ERa partially overcame the inhibitory effect of MBD2 when the ERE is unmethylated. Furthermore, serial chromatin immunoprecipitation assays indicated that MBD2 and ERa could simultaneously occupy the same pS2 DNA molecule; (iv) concomitant ectopic ERa expression and MBD2 depletion resulted in synergistic transcriptional stimulation, while the pS2 promoter remains methylated. Conclusions/Significance: MBD2 and ERa drive opposite effects on pS2 expression, which