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Tuning Transcription Factor Availability through Acetylation-Mediated Genomic Redistribution

Tuning Transcription Factor Availability through Acetylation-Mediated Genomic Redistribution

Title: Tuning Transcription Factor Availability through Acetylation-Mediated Genomic Redistribution
Author: Louphrasitthiphol, Pakavarin
Siddaway, Robert
Loffreda, Alessia
Pogenberg, Vivian
Friedrichsen, Hans
Schepsky, Alexander
Zeng, Zhiqiang
Lu, Min
Strub, Thomas
Freter, Rasmus
... 14 more authors Show all authors
Date: 2020-08-06
Language: English
Scope: 472-487.e10
University/Institute: Háskóli Íslands
University of Iceland
School: Heilbrigðisvísindasvið (HÍ)
School of Health Sciences (UI)
Department: Læknadeild (HÍ)
Faculty of Medicine (UI)
Series: Molecular Cell;79(3)
ISSN: 1097-2765
DOI: 10.1016/j.molcel.2020.05.025
Subject: 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

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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


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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This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

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