Differential regulation of the α-globin locus by Krüppel-like factor 3 in erythroid and non-erythroid cells
<p style="text-align:justify;"> <b> Background:</b> 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 K...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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BioMed Central
2014
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| _version_ | 1797067327622086656 |
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| author | Funnell, A Vernimmen, D Lim, W Mak, K Wienert, B Martyn, G Artuz, C Burdach, J Quinlan, K Higgs, D Whitelaw, E Pearson, R Crossley, M |
| author_facet | Funnell, A Vernimmen, D Lim, W Mak, K Wienert, B Martyn, G Artuz, C Burdach, J Quinlan, K Higgs, D Whitelaw, E Pearson, R Crossley, M |
| author_sort | Funnell, A |
| collection | OXFORD |
| description | <p style="text-align:justify;"> <b> Background:</b> 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.<br/><br/> <b>Results:</b> 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.<br/><br/> <b>Conclusions:</b> 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. </p> |
| first_indexed | 2024-03-06T21:54:41Z |
| format | Journal article |
| id | oxford-uuid:4c819e33-0ecd-4b0f-96d5-4d8ad3033a98 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T21:54:41Z |
| publishDate | 2014 |
| publisher | BioMed Central |
| record_format | dspace |
| spelling | oxford-uuid:4c819e33-0ecd-4b0f-96d5-4d8ad3033a982022-03-26T15:49:53ZDifferential regulation of the α-globin locus by Krüppel-like factor 3 in erythroid and non-erythroid cellsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:4c819e33-0ecd-4b0f-96d5-4d8ad3033a98EnglishSymplectic Elements at OxfordBioMed Central2014Funnell, AVernimmen, DLim, WMak, KWienert, BMartyn, GArtuz, CBurdach, JQuinlan, KHiggs, DWhitelaw, EPearson, RCrossley, M <p style="text-align:justify;"> <b> Background:</b> 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.<br/><br/> <b>Results:</b> 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.<br/><br/> <b>Conclusions:</b> 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. </p> |
| spellingShingle | Funnell, A Vernimmen, D Lim, W Mak, K Wienert, B Martyn, G Artuz, C Burdach, J Quinlan, K Higgs, D Whitelaw, E Pearson, R Crossley, M Differential regulation of the α-globin locus by Krüppel-like factor 3 in erythroid and non-erythroid cells |
| title | Differential regulation of the α-globin locus by Krüppel-like factor 3 in erythroid and non-erythroid cells |
| title_full | Differential regulation of the α-globin locus by Krüppel-like factor 3 in erythroid and non-erythroid cells |
| title_fullStr | Differential regulation of the α-globin locus by Krüppel-like factor 3 in erythroid and non-erythroid cells |
| title_full_unstemmed | Differential regulation of the α-globin locus by Krüppel-like factor 3 in erythroid and non-erythroid cells |
| title_short | Differential regulation of the α-globin locus by Krüppel-like factor 3 in erythroid and non-erythroid cells |
| title_sort | differential regulation of the α globin locus by kruppel like factor 3 in erythroid and non erythroid cells |
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