PUBLICATION
Tuning Transcription Factor Availability through Acetylation-Mediated Genomic Redistribution
- Authors
- 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.
- ID
- ZDB-PUB-200826-1
- Date
- 2020
- Source
- Molecular Cell 79: 472-487.e10 (Journal)
- Registered Authors
- Patton, E. Elizabeth
- Keywords
- DNA-binding affinity, E-box, MITF, acetylation, bHLH-LZ, melanocyte, melanoma, transcription factor
- MeSH Terms
-
- 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
- PubMed
- 32531202 Full text @ Mol. Cell
Citation
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. 79:472-487.e10.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping