Differential regulation of the α-globin locus by Krüppel-like Factor 3 in erythroid and non-erythroid cells.
| Autor: | Funnell AP, Vernimmen D, Lim WF, Mak KS, Wienert B, Martyn GE, Artuz CM, Burdach J, Quinlan KG, Higgs DR, Whitelaw E, Pearson RC, Crossley M; School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia. m.crossley@unsw.edu.au. |
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| Jazyk: | angličtina |
| Zdroj: | BMC molecular biology [BMC Mol Biol] 2014 May 16; Vol. 15, pp. 8. Date of Electronic Publication: 2014 May 16. |
| DOI: | 10.1186/1471-2199-15-8 |
| Abstrakt: | Background: Krüppel-like Factor 3 (KLF3) is a broadly expressed zinc-finger transcriptional repressor with diverse biological roles. During erythropoiesis, KLF3 acts as a feedback repressor of a set of genes that are activated by Krüppel-like Factor 1 (KLF1). Noting that KLF1 binds α-globin gene regulatory sequences during erythroid maturation, we sought to determine whether KLF3 also interacts with the α-globin locus to regulate transcription. Results: We found that expression of a human transgenic α-globin reporter gene is markedly up-regulated in fetal and adult erythroid cells of Klf3-/- mice. Inspection of the mouse and human α-globin promoters revealed a number of canonical KLF-binding sites, and indeed, KLF3 was shown to bind to these regions both in vitro and in vivo. Despite these observations, we did not detect an increase in endogenous murine α-globin expression in Klf3-/- erythroid tissue. However, examination of murine embryonic fibroblasts lacking KLF3 revealed significant de-repression of α-globin gene expression. This suggests that KLF3 may contribute to the silencing of the α-globin locus in non-erythroid tissue. Moreover, ChIP-Seq analysis of murine fibroblasts demonstrated that across the locus, KLF3 does not occupy the promoter regions of the α-globin genes in these cells, but rather, binds to upstream, DNase hypersensitive regulatory regions. Conclusions: These findings reveal that the occupancy profile of KLF3 at the α-globin locus differs in erythroid and non-erythroid cells. In erythroid cells, KLF3 primarily binds to the promoters of the adult α-globin genes, but appears dispensable for normal transcriptional regulation. In non-erythroid cells, KLF3 distinctly binds to the HS-12 and HS-26 elements and plays a non-redundant, albeit modest, role in the silencing of α-globin expression. |
| Databáze: | MEDLINE |
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