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Sumoylation of p45/NF-E2: Nuclear Positioning and Transcriptional Activation of the Mammalian ß-Like Globin Gene Locus

Institute of Genetics, National Yang-Ming University, Shih-Pai, Taipei 112, Taiwan, Republic of China,¹ Institute of Molecular Biology, Academia Sinica, Nankang, Taipei 115, Taiwan, Republic of China,² Institute of Life Sciences, National Defense University, Taipei, Taiwan, Republic of China,³ Laboratory of Gene Regulation and Development, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-5431,⁴ Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, Republic of China,⁵ Department of Biomedical Sciences, Chung Shan Medical and Dental College, Taichung, Taiwan, Republic of China⁶

Received 18 April 2005/ Returned for modification 18 May 2005/ Accepted 8 September 2005

NF-E2 is a transcription activator for the regulation of a number of erythroid- and megakaryocytic lineage-specific genes. Here we present evidence that the large subunit of mammalian NF-E2, p45, is sumoylated in vivo in human erythroid K562 cells and in mouse fetal liver. By in vitro sumoylation reaction and DNA transfection experiments, we show that the sumoylation occurs at lysine 368 (K368) of human p45/NF-E2. Furthermore, p45 sumoylation enhances the transactivation capability of NF-E2, and this is accompanied by an increase of the NF-E2 DNA binding affinity. More interestingly, we have found that in K562 cells, the ß-globin gene loci in the euchromatin regions are predominantly colocalized with the nuclear bodies promyelocytic leukemia protein (PML) oncogenic domains that are enriched with the PML, SUMO-1, RNA polymerase II, and sumoylatable p45/NF-E2. Chromatin immunoprecipitation assays further showed that the intact sumoylation site of p45/NF-E2 is required for its binding to the DNase I-hypersensitive sites of the ß-globin locus control region. Finally, we demonstrated by stable transfection assay that only the wild-type p45, but not its mutant form p45 (K368R), could efficiently rescue ß-globin gene expression in the p45-null, erythroid cell line CB3. These data together point to a model of mammalian ß-like globin gene activation by sumoylated p45/NF-E2 in erythroid cells.

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