Developmental silencing of human ζ-globin gene expression is mediated by the transcriptional repressor RREB1

Ruei Lin Chen, Yu Chi Chou, Yii Jenq Lan, Ting Shuo Huang, C. K.James Shen

研究成果: 雜誌貢獻文章同行評審

12 引文 斯高帕斯(Scopus)

摘要

The mammalian embryonic ζ-globin genes, including that of humans, are expressed at the early embryonic stage and then switched off during erythroid development. This autonomous silencing of the ζ-globin gene transcription is probably regulated by the cooperative work of various protein-DNA and protein-protein complexes formed at the ζ-globin promoter and its upstream enhancer (HS-40). We present data here indicating that a protein-binding motif, ZF2, contributes to the repression of the HS-40-regulated human ζ-promoter activity in erythroid cell lines and in transgenic mice. Combined site-directed mutagenesis and EMSA suggest that repression of the human ζ-globin promoter is mediated through binding of the zinc finger factor RREB1 to ZF2. This model is further supported by the observation that human ζ-globin gene transcription is elevated in the human erythroid K562 cell line or the primary erythroid culture upon RNA interference (RNAi)2 knockdown of RREB1 expression. These data together suggest that RREB1 is a putative repressor for the silencing of the mammalian ζ-globin genes during erythroid development. Because ζ-globin is a powerful inhibitor of HbS polymerization, our experiments have provided a foundation for therapeutic up-regulation of ζ-globin gene expression in patients with severe hemoglobinopathies.

原文英語
頁(從 - 到)10189-10197
頁數9
期刊Journal of Biological Chemistry
285
發行號14
DOIs
出版狀態已發佈 - 四月 2 2010
對外發佈

ASJC Scopus subject areas

  • 生物化學
  • 分子生物學
  • 細胞生物學

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