Global landscape of mouse and human cytokine transcriptional regulation

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.National Institutes of Health (NIH) [R00 GM114296 and R35 GM128625 to J.I.F.B., 5T32HL007501-34 to J.A.S.]; National Science Foundation [NSF-REU BIO-1659605 to M.M.]. Funding for open access charge: NIH [R35 GM128625]. (R00 GM114296 - National Institutes of Health (NIH); R35 GM128625 - National Institutes of Health (NIH); 5T32HL007501-34 - National Institutes of Health (NIH); NSF-REU BIO-1659605 - National Science Foundation; R35 GM128625 - NIH)Published versio

The Molecular Mechanisms Governing Shoot Stem Cell Maintenance and Organ Patterning by a Family of Transcription Factors in Arabidopsis thaliana

Genome duplication in eukaryotes and particularly in plant species has led to gene families with both redundant and specialized functions. How closely related transcription factor families compete to alter gene expression and ultimately manifest a morphological phenotype is a key biological question. In Arabidopsis, the Class III Homedomain-Leucine Zipper (HD-ZIPIII) transcription factor family controls many developmental processes, such as embryo patterning and shoot stem cell formation, through complex genetic interactions. However the specific molecular mechanisms behind these genetic observations remain unresolved. I have discovered that HD-ZIPIIIs collaboratively and antagonistically regulate entire pathways at multiple, sometimes opposing steps, which can occur on a stage, tissue or cell type specific level. I found that HD-ZIPIIIs form preferential heterodimers in planta, co-occupy hundreds of genomic locations and regulate target gene expression both positively and negatively. Transcriptional repression by HD-ZIPIIIs is correlated with the co-occupancy and association with the co-repressor TOPLESS. Finally, I uncovered a novel HD-ZIPIII protein interaction partner that exhibits a similar genome-wide DNA binding profile and transcriptional response and interacts with both TPL and the HD-ZIPIIIs and thus may bridge a transcriptional complex required for HD-ZIPIII-mediated repression. These results demonstrate how a highly related family of TFs can collectively regulate important developmental signaling networks and will help unravel the inherent complexities of TF family interrelationships at both the molecular and network level

The Molecular Mechanisms Governing Shoot Stem Cell Maintenance and Organ Patterning by a Family of Transcription Factors in Arabidopsis thaliana

Genome duplication in eukaryotes and particularly in plant species has led to gene families with both redundant and specialized functions. How closely related transcription factor families compete to alter gene expression and ultimately manifest a morphological phenotype is a key biological question. In Arabidopsis, the Class III Homedomain-Leucine Zipper (HD-ZIPIII) transcription factor family controls many developmental processes, such as embryo patterning and shoot stem cell formation, through complex genetic interactions. However the specific molecular mechanisms behind these genetic observations remain unresolved. I have discovered that HD-ZIPIIIs collaboratively and antagonistically regulate entire pathways at multiple, sometimes opposing steps, which can occur on a stage, tissue or cell type specific level. I found that HD-ZIPIIIs form preferential heterodimers in planta, co-occupy hundreds of genomic locations and regulate target gene expression both positively and negatively. Transcriptional repression by HD-ZIPIIIs is correlated with the co-occupancy and association with the co-repressor TOPLESS. Finally, I uncovered a novel HD-ZIPIII protein interaction partner that exhibits a similar genome-wide DNA binding profile and transcriptional response and interacts with both TPL and the HD-ZIPIIIs and thus may bridge a transcriptional complex required for HD-ZIPIII-mediated repression. These results demonstrate how a highly related family of TFs can collectively regulate important developmental signaling networks and will help unravel the inherent complexities of TF family interrelationships at both the molecular and network level