Developmental silencing of human zeta-globin gene expression is mediated by the transcriptional repressor RREB1
| Autor: | Yii Jenq Lan, Yu Chi Chou, Ruei Lin Chen, C. K.James Shen, Ting Shuo Huang |
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| Rok vydání: | 2010 |
| Předmět: |
Chromatin Immunoprecipitation
Blotting Western Molecular Sequence Data Repressor Electrophoretic Mobility Shift Assay Mice Transgenic Biology Regulatory Sequences Nucleic Acid Biochemistry Mice RNA interference hemic and lymphatic diseases Gene expression Transcriptional regulation Gene silencing Animals Humans Gene Regulation Gene Silencing RNA Messenger zeta-Globins RNA Small Interfering Promoter Regions Genetic Molecular Biology Regulation of gene expression Gene knockdown Binding Sites Base Sequence Reverse Transcriptase Polymerase Chain Reaction Gene Expression Regulation Developmental Promoter Cell Biology Molecular biology DNA-Binding Proteins Repressor Proteins Mutagenesis Site-Directed K562 Cells Transcription Factors |
| Zdroj: | The Journal of biological chemistry. 285(14) |
| ISSN: | 1083-351X |
| Popis: | The mammalian embryonic zeta-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 zeta-globin gene transcription is probably regulated by the cooperative work of various protein-DNA and protein-protein complexes formed at the zeta-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 zeta-promoter activity in erythroid cell lines and in transgenic mice. Combined site-directed mutagenesis and EMSA suggest that repression of the human zeta-globin promoter is mediated through binding of the zinc finger factor RREB1 to ZF2. This model is further supported by the observation that human zeta-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 zeta-globin genes during erythroid development. Because zeta-globin is a powerful inhibitor of HbS polymerization, our experiments have provided a foundation for therapeutic up-regulation of zeta-globin gene expression in patients with severe hemoglobinopathies. |
| Databáze: | OpenAIRE |
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