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

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

Author information

1
Department of Cellular and Molecular Medicine, School of Medicine, University of California San Diego, La Jolla, CA, 92037, USA.
2
Department of Medicine, School of Medicine, University of California San Diego, La Jolla, CA, 92037, USA.
3
Department of Bioengineering, Jacobs School of Engineering, University of California San Diego, La Jolla, CA, 92037, USA.
4
Faculty of Biology, Division of Evolutionary Biology, Ludwig-Maximilian University of Munich, Munich, 80539, Germany.
5
Department of Cellular and Molecular Medicine, School of Medicine, University of California San Diego, La Jolla, CA, 92037, USA. ckg@ucsd.edu.
6
Department of Medicine, School of Medicine, University of California San Diego, La Jolla, CA, 92037, USA. ckg@ucsd.edu.

Abstract

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.

PMID:
30679424
PMCID:
PMC6345992
DOI:
10.1038/s41467-018-08236-0
[Indexed for MEDLINE]
Free PMC Article

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