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Journal Articles Molecular Cell Year : 2020

Tuning Transcription Factor Availability through Acetylation-Mediated Genomic Redistribution

Min Lu
  • Function : Author
Eda Suer
  • Function : Author
Benjamin Thomas
  • Function : Author
  • PersonId : 755865
  • IdRef : 169847721
Mark Middleton
Xin Lu
Colin Goding

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.
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Dates and versions

hal-03445556 , version 1 (16-05-2022)

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Pakavarin Louphrasitthiphol, Robert Siddaway, Alessia Loffreda, Vivian Pogenberg, Hans Friedrichsen, et al.. Tuning Transcription Factor Availability through Acetylation-Mediated Genomic Redistribution. Molecular Cell, 2020, 79 (3), pp.472-487. ⟨10.1016/j.molcel.2020.05.025⟩. ⟨hal-03445556⟩
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