Tuning Transcription Factor Availability through Acetylation-Mediated Genomic Redistribution

Pakavarin Louphrasitthiphol, Robert Siddaway, Alessia Loffreda, Vivian Pogenberg, Hans Friedrichsen, Alexander Schepsky, Zhiqiang Zeng, Min Lu, Thomas Strub, Rasmus Freter, Richard Lisle, Eda Suer, Benjamin Thomas, Benjamin Schuster-Böckler, Panagis Filippakopoulos, Mark Middleton, Xin Lu, E. Elizabeth Patton, Irwin Davidson, Jean Philippe LambertMatthias Wilmanns, Eiríkur Steingrímsson, Davide Mazza, Colin R. Goding

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)472-487.e10
JournalMolecular Cell
Volume79
Issue number3
DOIs
Publication statusPublished - Aug 6 2020

Keywords

  • acetylation
  • bHLH-LZ
  • DNA-binding affinity
  • E-box
  • melanocyte
  • melanoma
  • MITF
  • transcription factor

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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