Titill: | Tuning Transcription Factor Availability through Acetylation-Mediated Genomic Redistribution |
Höfundur: |
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Útgáfa: | 2020-08-06 |
Tungumál: | Enska |
Umfang: | 472-487.e10 |
Háskóli/Stofnun: | Háskóli Íslands University of Iceland |
Svið: | Heilbrigðisvísindasvið (HÍ) School of Health Sciences (UI) |
Deild: | Læknadeild (HÍ) Faculty of Medicine (UI) |
Birtist í: | Molecular Cell;79(3) |
ISSN: | 1097-2765 |
DOI: | 10.1016/j.molcel.2020.05.025 |
Efnisorð: | Acetylation; bHLH-LZ; DNA-binding affinity; E-box; Melanocyte; Melanoma; MITF; Transcription factor; Sortuæxli; DNA-rannsóknir |
URI: | https://hdl.handle.net/20.500.11815/2240 |
Tilvitnun:Louphrasitthiphol, P., Siddaway, R., Loffreda, A., Pogenberg, V., Friedrichsen, H., Schepsky, A., Zeng, Z., Lu, M., Strub, T., Freter, R., Lisle, R., Suer, E., Thomas, B., Schuster-Böckler, B., Filippakopoulos, P., Middleton, M., Lu, X., Patton, E.E., Davidson, I., Lambert, J.-P., Wilmanns, M., Steingrímsson, E., Mazza, D., Goding, C.R., 2020. Tuning Transcription Factor Availability through Acetylation-Mediated Genomic Redistribution. Molecular Cell. doi:10.1016/j.molcel.2020.05.025
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Útdráttur:It is widely assumed that decreasing transcription factor DNA-binding affinity reduces transcription initiation by diminishing occupancy of sequence-specific regulatory elements. However, in vivo transcription factors find their binding sites while confronted with a large excess of low-affinity degenerate motifs. Here, using the melanoma lineage survival oncogene MITF as a model, we show that low-affinity binding sites act as a competitive reservoir in vivo from which transcription factors are released by mitogen-activated protein kinase (MAPK)-stimulated acetylation to promote increased occupancy of their regulatory elements. Consequently, a low-DNA-binding-affinity acetylation-mimetic MITF mutation supports melanocyte development and drives tumorigenesis, whereas a high-affinity non-acetylatable mutant does not. The results reveal a paradoxical acetylation-mediated molecular clutch that tunes transcription factor availability via genome-wide redistribution and couples BRAF to tumorigenesis. Our results further suggest that p300/CREB-binding protein-mediated transcription factor acetylation may represent a common mechanism to control transcription factor availability.
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Athugasemdir:Publisher's version (útgefin grein)
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Leyfi:This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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