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  • Tuning Transcription Factor Availability through Acetylation-Mediated Genomic Redistribution.

Tuning Transcription Factor Availability through Acetylation-Mediated Genomic Redistribution.

Molecular cell (2020-06-13)
Pakavarin Louphrasitthiphol, Robert Siddaway, Alessia Loffreda, Vivian Pogenberg, Hans Friedrichsen, Alexander Schepsky, Zhiqiang Zeng, Min Lu, Thomas Strub, Rasmus Freter, Richard Lisle, Eda Suer, Benjamin Thomas, Benjamin Schuster-Böckler, Panagis Filippakopoulos, Mark Middleton, Xin Lu, E Elizabeth Patton, Irwin Davidson, Jean-Philippe Lambert, Matthias Wilmanns, Eiríkur Steingrímsson, Davide Mazza, Colin R Goding
ABSTRACT

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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