Subcellular transport of EKLF and switch-on of murine adult βmaj globin gene transcription

Yu Chiau Shyu, Tung Liang Lee, Shau Ching Wen, Hsin Chen, Wei Yuan Hsiao, Xin Chen, JauLang Hwang, Che Kun James Shen

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Erythroid Krüppel-like factor (EKLF) is an essential transcription factor for mammalian β-like globin gene switching, and it specifically activates transcription of the adult β 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 βmaj 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 βmaj 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 βmaj is silenced. Remarkably, in a cultured mouse adult erythroleukemic (MEL) cell line, the activation of the βmaj 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 βmaj 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 β-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 β globin gene transcription.

Original languageEnglish
Pages (from-to)2309-2323
Number of pages15
JournalMolecular and Cellular Biology
Volume27
Issue number6
DOIs
Publication statusPublished - Mar 2007
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

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    Shyu, Y. C., Lee, T. L., Wen, S. C., Chen, H., Hsiao, W. Y., Chen, X., Hwang, J., & Shen, C. K. J. (2007). Subcellular transport of EKLF and switch-on of murine adult βmaj globin gene transcription. Molecular and Cellular Biology, 27(6), 2309-2323. https://doi.org/10.1128/MCB.01875-06