Journal
GENES & DEVELOPMENT
Volume 29, Issue 6, Pages 603-616Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.242842.114
Keywords
TWIST; bHLH transcription factor; WR domain; epithelial-mesenchymal transition
Categories
Funding
- National Institutes of Health (NIH) [DP2OD002420, 1RO1CA168689, 1R01CA174869]
- Sidney Kimmel Foundation for Cancer Research
- Hartwell Foundation
- Mary Kay Ash Charitable Foundation
- NIH [P30-CA010815, R01-CA129883, R01-CA163761, R01-CA167151, R01-CA175691, 1RO1HG004659]
- Department of Defence Breast Cancer Research Program [W81XWH-11-1-0494]
- Samuel Waxman Cancer Research Foundation
- Susan G. Komen for the Cure [KG-110708]
- Noreen O'Neill Foundation for Melanoma Research
- Ovarian Cancer Research Foundation [291009]
- NIH predoctoral training grant [5T32GM007752]
- NIH National Research Science Award [5F31GM090678]
- NIH training grant [5T32NCI09171]
- NIH Institutional Research and Academic Career Development Award training grant [5K12GM068524]
- NATIONAL CANCER INSTITUTE [P30CA010815, R01CA168689, T32CA009171, R01CA175691, R01CA163761, R01CA174869] Funding Source: NIH RePORTER
- NATIONAL HUMAN GENOME RESEARCH INSTITUTE [R01HG004659] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM007752, K12GM068524, F31GM090678] Funding Source: NIH RePORTER
- OFFICE OF THE DIRECTOR, NATIONAL INSTITUTES OF HEALTH [DP2OD002420] Funding Source: NIH RePORTER
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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.
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