Tuning Transcription Factor Availability through Acetylation-Mediated Genomic Redistribution
Beteiligte Einrichtungen
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.
Bibliografische Daten
Originalsprache | Englisch |
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ISSN | 1097-2765 |
DOIs | |
Status | Veröffentlicht - 06.08.2020 |
Anmerkungen des Dekanats
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
PubMed | 32531202 |
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