Journal of Biological Chemistry
Volume 286, Issue 43, 28 October 2011, Pages 37196-37206
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Gene Regulation
5-Aza-2′-deoxycytidine Activates Iron Uptake and Heme Biosynthesis by Increasing c-Myc Nuclear Localization and Binding to the E-boxes of Transferrin Receptor 1 (TfR1) and Ferrochelatase (Fech) Genes*

https://doi.org/10.1074/jbc.M111.258129Get rights and content
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The hypomethylating agent 5-aza-2′-deoxycytidine (5-aza-CdR) and its derivatives have been successfully used for the treatment of myelodysplastic syndromes, and they frequently improve the anemia that usually accompanies these disorders. However, the molecular mechanisms underlying this action remain poorly understood. In this study, we used two erythroid models, murine erythroid leukemia cells and erythroid burst-forming unit-derived erythroblasts, to show that 5-aza-CdR induced erythroid differentiation and increased the expression of transferrin receptor 1 (TfR1) and ferrochelatase (Fech), thereby increasing iron uptake and heme biosynthesis. We have identified new regulatory E-boxes that lie outside of CpG islands in the TfR1 and Fech promoters, and the methylation status of these sites can be altered by 5-aza-CdR treatment. This in turn altered the binding of the transcription factor c-Myc to these promoter elements. Furthermore, 5-aza-CdR promoted the nuclear translocation of c-Myc and its binding to Max to form functional complexes. The coordinated actions of 5-aza-CdR on the methylation status of the target genes and in stimulating the nuclear translocation of c-Myc provide new molecular insights into the regulation of E-boxes and explain, at least in part, the increased erythroid response to 5-aza-CdR treatment.

DNA Methylation
Erythropoiesis
Heme
Protein DNA-Interaction
Transcription Regulation
5-Aza-CdR
TfR1
c-Myc
Myelodysplastic Syndromes

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*

This work was supported by National Basic Research Program of China (973 program) Grants 2012CB934000, 2011CB933400, and 2010CB912802 and National Natural Science Foundation of China Grants 30900278 and 10979011.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S4 and S5.

2

Recipient of a Senior Research Fellowship from the National Health and Medical Research Council of Australia.

1

Both authors contributed equally to this work.