An evolutionarily conserved DNA architecture determines target specificity of the TWIST family bHLH transcription factors
© 2015 Chang et al.; Published by Cold Spring Harbor Laboratory Press..
Basic helix-loop-helix (bHLH) transcription factors recognize the canonical E-box (CANNTG) to regulate gene transcription; however, given the prevalence of E-boxes in a genome, it has been puzzling how individual bHLH proteins selectively recognize E-box sequences on their targets. TWIST is a bHLH transcription factor that promotes epithelial-mesenchymal transition (EMT) during development and tumor metastasis. High-resolution mapping of TWIST occupancy in human and Drosophila genomes reveals that TWIST, but not other bHLH proteins, recognizes a unique double E-box motif with two E-boxes spaced preferentially by 5 nucleotides. Using molecular modeling and binding kinetic analyses, we found that the strict spatial configuration in the double E-box motif aligns two TWIST-E47 dimers on the same face of DNA, thus providing a high-affinity site for a highly stable intramolecular tetramer. Biochemical analyses showed that the WR domain of TWIST dimerizes to mediate tetramer formation, which is functionally required for TWIST-induced EMT. These results uncover a novel mechanism for a bHLH transcription factor to recognize a unique spatial configuration of E-boxes to achieve target specificity. The WR-WR domain interaction uncovered here sets an example of target gene specificity of a bHLH protein being controlled allosterically by a domain outside of the bHLH region.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2015 |
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| Erschienen: |
2015 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:29 |
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| Enthalten in: |
Genes & development - 29(2015), 6 vom: 15. März, Seite 603-16 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Chang, Andrew T [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 07.10.2015 Date Revised 13.11.2018 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1101/gad.242842.114 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM246999543 |
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| 100 | 1 | |a Chang, Andrew T |e verfasserin |4 aut | |
| 245 | 1 | 3 | |a An evolutionarily conserved DNA architecture determines target specificity of the TWIST family bHLH transcription factors |
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| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2015 Chang et al.; Published by Cold Spring Harbor Laboratory Press. | ||
| 520 | |a Basic helix-loop-helix (bHLH) transcription factors recognize the canonical E-box (CANNTG) to regulate gene transcription; however, given the prevalence of E-boxes in a genome, it has been puzzling how individual bHLH proteins selectively recognize E-box sequences on their targets. TWIST is a bHLH transcription factor that promotes epithelial-mesenchymal transition (EMT) during development and tumor metastasis. High-resolution mapping of TWIST occupancy in human and Drosophila genomes reveals that TWIST, but not other bHLH proteins, recognizes a unique double E-box motif with two E-boxes spaced preferentially by 5 nucleotides. Using molecular modeling and binding kinetic analyses, we found that the strict spatial configuration in the double E-box motif aligns two TWIST-E47 dimers on the same face of DNA, thus providing a high-affinity site for a highly stable intramolecular tetramer. Biochemical analyses showed that the WR domain of TWIST dimerizes to mediate tetramer formation, which is functionally required for TWIST-induced EMT. These results uncover a novel mechanism for a bHLH transcription factor to recognize a unique spatial configuration of E-boxes to achieve target specificity. The WR-WR domain interaction uncovered here sets an example of target gene specificity of a bHLH protein being controlled allosterically by a domain outside of the bHLH region | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
| 650 | 4 | |a TWIST | |
| 650 | 4 | |a WR domain | |
| 650 | 4 | |a bHLH transcription factor | |
| 650 | 4 | |a epithelial–mesenchymal transition | |
| 650 | 7 | |a Drosophila Proteins |2 NLM | |
| 650 | 7 | |a Twist-Related Protein 1 |2 NLM | |
| 700 | 1 | |a Liu, Yuanjie |e verfasserin |4 aut | |
| 700 | 1 | |a Ayyanathan, Kasirajan |e verfasserin |4 aut | |
| 700 | 1 | |a Benner, Chris |e verfasserin |4 aut | |
| 700 | 1 | |a Jiang, Yike |e verfasserin |4 aut | |
| 700 | 1 | |a Prokop, Jeremy W |e verfasserin |4 aut | |
| 700 | 1 | |a Paz, Helicia |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Dong |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Hai-Ri |e verfasserin |4 aut | |
| 700 | 1 | |a Fu, Xiang-Dong |e verfasserin |4 aut | |
| 700 | 1 | |a Rauscher, Frank J |c 3rd |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Jing |e verfasserin |4 aut | |
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| 773 | 1 | 8 | |g volume:29 |g year:2015 |g number:6 |g day:15 |g month:03 |g pages:603-16 |
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