Tuning Transcription Factor Availability through Acetylation-Mediated Genomic Redistribution.
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 EE., Davidson I., Lambert J-P., Wilmanns M., Steingrímsson E., Mazza D., Goding CR.
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.