Cooperation between bHLH transcription factors and histones for DNA access. Academic Article uri icon


  • 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.

published proceedings

  • Nature

author list (cited authors)

  • Michael, A. K., Stoos, L., Crosby, P., Eggers, N., Nie, X. Y., Makasheva, K., ... Thom, N. H.

complete list of authors

  • Michael, Alicia K||Stoos, Lisa||Crosby, Priya||Eggers, Nikolas||Nie, Xinyu Y||Makasheva, Kristina||Minnich, Martina||Healy, Kelly L||Weiss, Joscha||Kempf, Georg||Cavadini, Simone||Kater, Lukas||Seebacher, Jan||Vecchia, Luca||Chakraborty, Deyasini||Isbel, Luke||Grand, Ralph S||Andersch, Florian||Fribourgh, Jennifer L||Schübeler, Dirk||Zuber, Johannes||Liu, Andrew C||Becker, Peter B||Fierz, Beat||Partch, Carrie L||Menet, Jerome S||Thomä, Nicolas H

publication date

  • July 2023

published in