Tuning Transcription Factor Availability through Acetylation-Mediated Genomic Redistribution.
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
Melanoma
/ genetics
Mice
Mice, Nude
Microphthalmia-Associated Transcription Factor
/ chemistry
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
Zebrafish
DNA-binding affinity
E-box
MITF
acetylation
bHLH-LZ
melanocyte
melanoma
transcription factor
Journal
Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571
Informations de publication
Date de publication:
06 08 2020
06 08 2020
Historique:
received:
02
10
2019
revised:
01
04
2020
accepted:
19
05
2020
pubmed:
13
6
2020
medline:
26
8
2020
entrez:
13
6
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32531202
pii: S1097-2765(20)30345-2
doi: 10.1016/j.molcel.2020.05.025
pmc: PMC7427332
pii:
doi:
Substances chimiques
MITF protein, human
0
Microphthalmia-Associated Transcription Factor
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
472-487.e10Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00007/9
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/N010051/1
Pays : United Kingdom
Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests The authors declare no competing interests.
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