Tuning Transcription Factor Availability through Acetylation-Mediated Genomic Redistribution

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 dege...

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Vydáno v:	Molecular cell Ročník 79; číslo 3; s. 472
Hlavní autoři:	Louphrasitthiphol, Pakavarin, Siddaway, Robert, Loffreda, Alessia, Pogenberg, Vivian, Friedrichsen, Hans, Schepsky, Alexander, Zeng, Zhiqiang, Lu, Min, Strub, Thomas, Freter, Rasmus, Lisle, Richard, Suer, Eda, Thomas, Benjamin, Schuster-Böckler, Benjamin, Filippakopoulos, Panagis, Middleton, Mark, Lu, Xin, Patton, E Elizabeth, Davidson, Irwin, Lambert, Jean-Philippe, Wilmanns, Matthias, Steingrímsson, Eiríkur, Mazza, Davide, Goding, Colin R
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 06.08.2020
Témata:	Acetylation Amino Acid Sequence Animals Binding Sites Cell Line, Tumor Conserved Sequence Enhancer Elements, Genetic Female Gene Expression Regulation, Neoplastic Genome Heterografts Humans Male Melanocytes - metabolism Melanocytes - pathology Melanoma - genetics Melanoma - metabolism Melanoma - pathology Mice Mice, Nude Microphthalmia-Associated Transcription Factor - chemistry Microphthalmia-Associated Transcription Factor - genetics Microphthalmia-Associated Transcription Factor - metabolism Nucleotide Motifs Promoter Regions, Genetic Protein Binding Protein Interaction Domains and Motifs Protein Processing, Post-Translational Sequence Alignment Sequence Homology, Amino Acid Skin Neoplasms - genetics Skin Neoplasms - metabolism Skin Neoplasms - pathology Zebrafish acetylation E-box transcription factor melanocyte DNA-binding affinity bHLH-LZ melanoma MITF
ISSN:	1097-4164, 1097-4164
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Popis
Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1097-4164 1097-4164
DOI:	10.1016/j.molcel.2020.05.025