Biology subjects

Santoso, C. S.

Publications and source records attributed to Santoso, C. S..

3 recordsLinked to original sources

bioRxiv2020

In vitro Targeting of Transcription Factors to Control the Cytokine Release Syndrome in COVID-19

Treatment of the cytokine release syndrome (CRS) has become an important part of rescuing hospitalized COVID-19 patients. Here, we systematically explored the transcriptional regulators of inflammatory cytokines involved in the COVID-19 CRS to identify candidate transcription factors (TFs) for therapeutic targeting using approved drugs. We integrated a resource of TF-cytokine gene interactions with single-cell RNA-seq expression data from bronchoalveolar lavage fluid cells of COVID-19 patients. We found 581 significantly correlated interactions, between 95 TFs and 16 cytokines upregulated in the COVID-19 patients, that may contribute to pathogenesis of the disease. Among these, we identified 19 TFs that are targets of FDA approved drugs. We investigated the potential therapeutic effect of 10 drugs and 25 drug combinations on inflammatory cytokine production in peripheral blood mononuclear cells, which revealed two drugs that inhibited cytokine production and numerous combinations that show synergistic efficacy in downregulating cytokine production. Further studies of these candidate repurposable drugs could lead to a therapeutic regimen to treat the CRS in COVID-19 patients.

immunology↗

bioRxiv2018

Uncovering human transcription factor interactions associated with genetic variants, novel DNA motifs, and repetitive elements using enhanced yeast one-hybrid assays

Identifying transcription factor (TF) binding to noncoding variants, uncharacterized DNA motifs, and repetitive genomic elements has been technically and computationally challenging. Current experimental methods, such as chromatin immunoprecipitation, generally test one TF at a time, and computational motif algorithms often lead to false positive and negative predictions. To address these limitations, we developed two approaches based on enhanced yeast one-hybrid assays. The first approach interrogates the binding of >1,000 human TFs to repetitive DNA elements, while the second evaluates TF binding to single nucleotide variants, short insertions and deletions (indels), and novel DNA motifs. Using the first approach, we detected the binding of 75 TFs, including several nuclear hormone receptors and ETS factors, to the highly repetitive Alu elements. Using the second approach, we identified cancer-associated changes in TF binding, including gain of interactions involving ETS TFs and loss of interactions involving KLF TFs to different mutations in the TERT promoter, and gain of a MYB interaction with an 18 bp indel in the TAL1 super-enhancer. Additionally, we identified the TFs that bind to three uncharacterized DNA motifs identified in DNase footprinting assays. We anticipate that these approaches will expand our capabilities to study genetic variation and under-characterized genomic regions.

genomics↗

bioRxiv2018

Global landscape of mouse and human cytokine transcriptional regulation

Cytokines 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 review three decades of studies to generate a comprehensive database reporting 843 and 647 interactions between TFs and cytokines genes, in human and mouse respectively (http://cytreg.bu.edu). We provide a historic perspective on cytokine regulation discussing research trends and biases. More importantly, by integrating this comprehensive database with other functional datasets, we determine 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. Finally, we illustrate the use of our database as a blueprint to study TF-cytokine regulatory axes in autoimmune diseases.

immunology↗