Háskóli ÍslandsUniversity of IcelandLouphrasitthiphol, PakavarinSiddaway, RobertLoffreda, AlessiaPogenberg, VivianFriedrichsen, HansSchepsky, AlexanderZeng, ZhiqiangLu, MinStrub, ThomasFreter, RasmusLisle, RichardSuer, EdaThomas, BenjaminSchuster-Böckler, BenjaminFilippakopoulos, PanagisMiddleton, MarkLu, XinPatton, E. ElizabethDavidson, IrwinLambert, Jean-PhilippeWilmanns, MatthiasSteingrimsson, EirikurMazza, DavideGoding, Colin R.2020-11-242020-11-242020-08-06Louphrasitthiphol, 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.2020.05.0251097-2765https://hdl.handle.net/20.500.11815/2240Publisher's version (útgefin grein)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.472-487.e10eninfo:eu-repo/semantics/openAccessAcetylationbHLH-LZDNA-binding affinityE-boxMelanocyteMelanomaMITFTranscription factorSortuæxliDNA-rannsóknirinfo:eu-repo/semantics/articleMolecular Cell10.1016/j.molcel.2020.05.025