Diverse motif ensembles specify non-redundant DNA binding activities of AP-1 family members in macrophages

Nat Commun. 2019 Jan 24;10(1):414. doi: 10.1038/s41467-018-08236-0.


Mechanisms by which members of the AP-1 family of transcription factors play non-redundant biological roles despite recognizing the same DNA sequence remain poorly understood. To address this question, here we investigate the molecular functions and genome-wide DNA binding patterns of AP-1 family members in primary and immortalized mouse macrophages. ChIP-sequencing shows overlapping and distinct binding profiles for each factor that were remodeled following TLR4 ligation. Development of a machine learning approach that jointly weighs hundreds of DNA recognition elements yields dozens of motifs predicted to drive factor-specific binding profiles. Machine learning-based predictions are confirmed by analysis of the effects of mutations in genetically diverse mice and by loss of function experiments. These findings provide evidence that non-redundant genomic locations of different AP-1 family members in macrophages largely result from collaborative interactions with diverse, locus-specific ensembles of transcription factors and suggest a general mechanism for encoding functional specificities of their common recognition motif.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 3
  • Animals
  • Base Sequence
  • Binding Sites / genetics
  • Cell Line
  • DNA / metabolism*
  • Gene Expression Profiling
  • Gene Expression Regulation / genetics
  • Gene Knockout Techniques
  • Genes, Overlapping
  • Genome*
  • Lipopolysaccharides / pharmacology
  • Macrophages / metabolism*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mutation
  • Nucleotide Motifs
  • Protein Domains
  • RNA, Messenger / metabolism
  • Sequence Alignment
  • Toll-Like Receptor 4 / metabolism
  • Transcription Factor AP-1 / genetics*
  • Transcription Factor AP-1 / metabolism*


  • Activating Transcription Factor 3
  • Atf3 protein, mouse
  • Kdo2-lipid A
  • Lipopolysaccharides
  • RNA, Messenger
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Transcription Factor AP-1
  • DNA