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Diverse motif ensembles specify non-redundant DNA binding activities of AP-1 family members in macrophages.
Department of Cellular and Molecular Medicine, School of Medicine, University of California San Diego, La Jolla, CA, 92037, USA.
Department of Cellular and Molecular Medicine, School of Medicine, University of California San Diego, La Jolla, CA, 92037, USA.
Department of Cellular and Molecular Medicine, School of Medicine, University of California San Diego, La Jolla, CA, 92037, USA.
Department of Medicine, School of Medicine, University of California San Diego, La Jolla, CA, 92037, USA.
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2019 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, no 1, article id 414Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2019. Vol. 10, no 1, article id 414
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Medical and Health Sciences
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URN: urn:nbn:se:liu:diva-154612DOI: 10.1038/s41467-018-08236-0PubMedID: 30679424OAI: oai:DiVA.org:liu-154612DiVA, id: diva2:1290798
Available from: 2019-02-21 Created: 2019-02-21 Last updated: 2019-03-15

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