Low-affinity transcription factor binding sites shape morphogen responses and enhancer evolution
In the era of functional genomics, the role of transcription factor (TF)-DNA binding affinity is of increasing interest: for example, it has recently been proposed that low-affinity genomic binding events, though frequent, are functionally irrelevant. Here, we investigate the role of binding site affinity in the transcriptional interpretation of Hedgehog (Hh) morphogen gradients. We noted that enhancers of several Hh-responsive Drosophila genes have low predicted affinity for Ci, the Gli family TF that transduces Hh signalling in the fly. Contrary to our initial hypothesis, improving the affinity of Ci/Gli sites in enhancers of dpp, wingless and stripe, by transplanting optimal sites from the patched gene, did not result in ectopic responses to Hh signalling. Instead, we found that these enhancers require low-affinity binding sites for normal activation in regions of relatively low signalling. When Ci/Gli sites in these enhancers were altered to improve their binding affinity, we observed patterning defects in the transcriptional response that are consistent with a switch from Ci-mediated activation to Ci-mediated repression. Synthetic transgenic reporters containing isolated Ci/Gli sites confirmed this finding in imaginal discs. We propose that the requirement for gene activation by Ci in the regions of low-to-moderate Hh signalling results in evolutionary pressure favouring weak binding sites in enhancers of certain Hh target genes.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2013 |
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| Erschienen: |
2013 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:368 |
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| Enthalten in: |
Philosophical transactions of the Royal Society of London. Series B, Biological sciences - 368(2013), 1632 vom: 19. Dez., Seite 20130018 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Ramos, Andrea I [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 06.07.2014 Date Revised 21.10.2021 published: Electronic-Print Citation Status MEDLINE |
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| doi: |
10.1098/rstb.2013.0018 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM232534381 |
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| 245 | 1 | 0 | |a Low-affinity transcription factor binding sites shape morphogen responses and enhancer evolution |
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| 500 | |a published: Electronic-Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a In the era of functional genomics, the role of transcription factor (TF)-DNA binding affinity is of increasing interest: for example, it has recently been proposed that low-affinity genomic binding events, though frequent, are functionally irrelevant. Here, we investigate the role of binding site affinity in the transcriptional interpretation of Hedgehog (Hh) morphogen gradients. We noted that enhancers of several Hh-responsive Drosophila genes have low predicted affinity for Ci, the Gli family TF that transduces Hh signalling in the fly. Contrary to our initial hypothesis, improving the affinity of Ci/Gli sites in enhancers of dpp, wingless and stripe, by transplanting optimal sites from the patched gene, did not result in ectopic responses to Hh signalling. Instead, we found that these enhancers require low-affinity binding sites for normal activation in regions of relatively low signalling. When Ci/Gli sites in these enhancers were altered to improve their binding affinity, we observed patterning defects in the transcriptional response that are consistent with a switch from Ci-mediated activation to Ci-mediated repression. Synthetic transgenic reporters containing isolated Ci/Gli sites confirmed this finding in imaginal discs. We propose that the requirement for gene activation by Ci in the regions of low-to-moderate Hh signalling results in evolutionary pressure favouring weak binding sites in enhancers of certain Hh target genes | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
| 650 | 4 | |a Ci/Gli | |
| 650 | 4 | |a binding affinity | |
| 650 | 4 | |a enhancers | |
| 650 | 4 | |a gene regulation | |
| 650 | 4 | |a hedgehog signalling | |
| 650 | 4 | |a morphogen gradient | |
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| 650 | 7 | |a Drosophila Proteins |2 NLM | |
| 650 | 7 | |a Hedgehog Proteins |2 NLM | |
| 650 | 7 | |a Transcription Factors |2 NLM | |
| 650 | 7 | |a ci protein, Drosophila |2 NLM | |
| 700 | 1 | |a Barolo, Scott |e verfasserin |4 aut | |
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