Tuning Transcription Factor Availability through Acetylation-Mediated Genomic Redistribution

Louphrasitthiphol P., Siddaway R., Loffreda A., Pogenberg V., Friedrichsen H., Schepsky A., ...Daha Fazla

MOLECULAR CELL, cilt.79, sa.3, ss.472-497, 2020 (SCI-Expanded) identifier identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 79 Sayı: 3
  • Basım Tarihi: 2020
  • Doi Numarası: 10.1016/j.molcel.2020.05.025
  • Dergi Adı: MOLECULAR CELL
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, Aquatic Science & Fisheries Abstracts (ASFA), BIOSIS, Biotechnology Research Abstracts, Chemical Abstracts Core, EMBASE, MEDLINE, DIALNET
  • Sayfa Sayıları: ss.472-497
  • Acıbadem Mehmet Ali Aydınlar Üniversitesi Adresli: Hayır

Özet

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.