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Molecular and Cellular Biology, March 2007, p. 2309-2323, Vol. 27, No. 6
0270-7306/07/$08.00+0     doi:10.1128/MCB.01875-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Subcellular Transport of EKLF and Switch-On of Murine Adult ßmaj Globin Gene Transcription{triangledown}

Yu-Chiau Shyu,1 Tung-Liang Lee,1,2 Shau-Ching Wen,1 Hsin Chen,1 Wei-Yuan Hsiao,1 Xin Chen,1,{dagger} JauLang Hwang,1 and Che-Kun James Shen1,2*

Institute of Molecular Biology, Academia Sinica, Nankang, Taipei 115, Taiwan, Republic of China,1 Institute of Life Sciences, National Defense University, Nei-hu, Taipei 114, Taiwan, Republic of China2

Received 5 October 2006/ Returned for modification 15 November 2006/ Accepted 2 January 2007

Erythroid Krüppel-like factor (EKLF) is an essential transcription factor for mammalian ß-like globin gene switching, and it specifically activates transcription of the adult ß globin gene through binding of its zinc fingers to the promoter. It has been a puzzle that in the mouse, despite its expression throughout the erythroid development, EKLF activates the adult ßmaj globin promoter only in erythroid cells beyond the stage of embryonic day 10.5 (E10.5) but not before. We show here that expression of the mouse ßmaj globin gene in the aorta-gonad-mesonephros region of E10.5 embryos and in the E14.5 fetal liver is accompanied by predominantly nuclear localization of EKLF. In contrast, EKLF is mainly cytoplasmic in the erythroid cells of E9.5 blood islands in which ßmaj is silenced. Remarkably, in a cultured mouse adult erythroleukemic (MEL) cell line, the activation of the ßmaj globin gene by dimethyl sulfoxide (DMSO) or hexamethylene-bis-acetamide (HMBA) induction is also paralleled by a shift of the subcellular location of EKLF from the cytoplasm to the nucleus. Blockage of the nuclear import of EKLF in DMSO-induced MEL cells with a nuclear export inhibitor repressed the transcription of the ßmaj globin gene. Transient transfection experiments further indicated that the full-sequence context of EKLF was required for the regulation of its subcellular locations in MEL cells during DMSO induction. Finally, in both the E14.5 fetal liver cells and induced MEL cells, the ß-like globin locus is colocalized the PML oncogene domain nuclear body, and concentrated with EKLF, RNA polymerase II, and the splicing factor SC35. These data together provide the first evidence that developmental stage- and differentiation state-specific regulation of the nuclear transport of EKLF might be one of the steps necessary for the switch-on of the mammalian adult ß globin gene transcription.

* Corresponding author. Mailing address: Institute of Molecular Biology, Academia Sinica, Nankang, Taipei 115, Taiwan, Republic of China. Phone: 886-2-27824188. Fax: 886-2-27884177. E-mail: ckshen{at}imb.sinica.edu.tw.

{triangledown} Published ahead of print on 22 January 2007.

{dagger} Present address: Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan Town, Miaoli County 350, Taiwan, Republic of China.

Molecular and Cellular Biology, March 2007, p. 2309-2323, Vol. 27, No. 6
0270-7306/07/$08.00+0     doi:10.1128/MCB.01875-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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