Cooperation between bHLH transcription factors and histones for DNA access

Nature. 2023 Jul;619(7969):385-393. doi: 10.1038/s41586-023-06282-3. Epub 2023 Jul 5.


The basic helix-loop-helix (bHLH) family of transcription factors recognizes DNA motifs known as E-boxes (CANNTG) and includes 108 members1. Here we investigate how chromatinized E-boxes are engaged by two structurally diverse bHLH proteins: the proto-oncogene MYC-MAX and the circadian transcription factor CLOCK-BMAL1 (refs. 2,3). Both transcription factors bind to E-boxes preferentially near the nucleosomal entry-exit sites. Structural studies with engineered or native nucleosome sequences show that MYC-MAX or CLOCK-BMAL1 triggers the release of DNA from histones to gain access. Atop the H2A-H2B acidic patch4, the CLOCK-BMAL1 Per-Arnt-Sim (PAS) dimerization domains engage the histone octamer disc. Binding of tandem E-boxes5-7 at endogenous DNA sequences occurs through direct interactions between two CLOCK-BMAL1 protomers and histones and is important for circadian cycling. At internal E-boxes, the MYC-MAX leucine zipper can also interact with histones H2B and H3, and its binding is indirectly enhanced by OCT4 elsewhere on the nucleosome. The nucleosomal E-box position and the type of bHLH dimerization domain jointly determine the histone contact, the affinity and the degree of competition and cooperativity with other nucleosome-bound factors.

MeSH terms

  • ARNTL Transcription Factors / genetics
  • Allosteric Regulation
  • Basic Helix-Loop-Helix Transcription Factors* / metabolism
  • CLOCK Proteins / chemistry
  • CLOCK Proteins / metabolism
  • DNA* / genetics
  • DNA* / metabolism
  • Helix-Loop-Helix Motifs / genetics
  • Histones* / chemistry
  • Histones* / metabolism
  • Leucine Zippers
  • Nucleosomes / chemistry
  • Nucleosomes / genetics
  • Nucleosomes / metabolism
  • Octamer Transcription Factor-3 / metabolism
  • Protein Binding
  • Protein Multimerization
  • Proto-Oncogene Proteins c-myc / chemistry
  • Proto-Oncogene Proteins c-myc / metabolism


  • ARNTL Transcription Factors
  • Basic Helix-Loop-Helix Transcription Factors
  • DNA
  • Histones
  • Nucleosomes
  • CLOCK Proteins
  • Proto-Oncogene Proteins c-myc
  • Myc associated factor X
  • Octamer Transcription Factor-3