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Fonseca, Gregory J.; Tao, Jenhan; Westin, Emma M.; Duttke, Sascha H.; Spann, Nathanael J.; Strid, Tobias; Shen, Zeyang; Stender, Joshua D.; Sakai, Mashito; Link, Verena M.; Benner, Christopher and Glass, Christopher K. (2019): Diverse motif ensembles specify non-redundant DNA binding activities of AP-1 family members in macrophages. In: Nature Communications, Vol. 10, 414 [PDF, 2MB]


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.

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