Global landscape of mouse and human cytokine transcriptional regulation
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Date
2018-10-12
Authors
Pro, Sebastian Carrasco
Imedio, Alvaro Dafonte
Santoso, Clarissa Stephanie
Gan, Kok Ann
Sewell, Jared Allan
Martinez, Melissa
Sereda, Rebecca
Mehta, Shivani
Version
Published version
OA Version
Citation
Sebastian Carrasco Pro, Alvaro Dafonte Imedio, Clarissa Stephanie Santoso, Kok Ann Gan, Jared Allan Sewell, Melissa Martinez, Rebecca Sereda, Shivani Mehta, Juan Ignacio Fuxman Bass. 2018. "Global landscape of mouse and human cytokine transcriptional regulation." NUCLEIC ACIDS RESEARCH, Volume 46, Issue 18, pp. 9321 - 9337 (17). https://doi.org/10.1093/nar/gky787
Abstract
Cytokines are cell-to-cell signaling proteins that play a central role in immune development, pathogen responses, and diseases. Cytokines are highly regulated at the transcriptional level by combinations of transcription factors (TFs) that recruit cofactors and the transcriptional machinery. Here, we mined through three decades of studies to generate a comprehensive database, CytReg, reporting 843 and 647 interactions between TFs and cytokine genes, in human and mouse respectively. By integrating CytReg with other functional datasets, we determined general principles governing the transcriptional regulation of cytokine genes. In particular, we show a correlation between TF connectivity and immune phenotype and disease, we discuss the balance between tissue-specific and pathogen-activated TFs regulating each cytokine gene, and cooperativity and plasticity in cytokine regulation. We also illustrate the use of our database as a blueprint to predict TF–disease associations and identify potential TF–cytokine regulatory axes in autoimmune diseases. Finally, we discuss research biases in cytokine regulation studies, and use CytReg to predict novel interactions based on co-expression and motif analyses which we further validated experimentally. Overall, this resource provides a framework for the rational design of future cytokine gene regulation studies.
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Attribution 4.0 International