Global landscape of mouse and human cytokine transcriptional regulation

Pro, Sebastian Carrasco; Imedio, Alvaro Dafonte; Santoso, Clarissa Stephanie; Gan, Kok Ann; Sewell, Jared Allan; Martinez, Mélissa; Sereda, Rebecca; Mehta, Suresh L.; Bass, Juan I. Fuxman

doi:10.1093/nar/gky787

Cited by 47 publications

(47 citation statements)

References 81 publications

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“…Secondly, we further used a set of 113 human cytokines to quantify host inflammation responses between three viruses. The 113 cytokines from the CytoReg database were often cited by various publications and play a primary role in the immune system [25].…”

Section: Mers-covmentioning

confidence: 99%

Comparative transcriptome analysis reveals the intensive early-stage responses of host cells to SARS-CoV-2 infection

Sun

et al. 2020

Preprint

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a widespread outbreak of highly pathogenic COVID-19. It is therefore important and timely to characterize interactions between the virus and host cell at the molecular level to understand its disease pathogenesis. To gain insights, we performed high-throughput sequencing that generated time-series data simultaneously for bioinformatics analysis of virus genomes and host transcriptomes implicated in SARS-CoV-2 infection. Our analysis results showed that the rapid growth of the virus was accompanied by an early intensive response of host genes. We also systematically compared the molecular footprints of the host cells in response to SARS-CoV-2, SARS-CoV and MERS-CoV. Upon infection, SARS-CoV-2 induced hundreds of up-regulated host genes hallmarked by a significant cytokine production followed by virus-specific host antiviral responses. While the cytokine and antiviral responses triggered by SARS-CoV and MERS-CoV were only observed during the late stage of infection, the host antiviral responses during the SARS-CoV-2 infection were gradually enhanced lagging behind the production of cytokine. The early rapid host responses were potentially attributed to the high efficiency of SARS-CoV-2 entry into host cells, underscored by evidence of a remarkably up-regulated gene expression of TPRMSS2 soon after infection. Taken together, our findings provide novel molecular insights into the mechanisms underlying the infectivity and pathogenicity of SARS-CoV-2.

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Section: Mers-covmentioning

confidence: 99%

Comparative transcriptome analysis reveals the intensive early-stage responses of host cells to SARS-CoV-2 infection

Sun

et al. 2020

Preprint

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“…Research conducted for more than three decades has identified 170 TFs that bind to the transcriptional control regions and/or regulate 95 (of ~140) human cytokine genes (Carrasco Pro et al, 2018). This includes TFs that are activated by pathogen signals (e.g., NF-κB, AP-1, and IRFs), stress signals (e.g., HIF1A, TP53, and HSF1), cytokine signals (e.g., STATs and NF-κB), as well as lineage factors (e.g., SPI1 and CEBPA).…”

Section: Introductionmentioning

confidence: 99%

“…However, analysis of this literature-derived human cytokine protein-DNA interaction (PDI) network suggests that this network is largely incomplete. For instance, no PDIs have been reported for nearly 30% of the cytokine genes, and new TFs and PDIs in the cytokine PDI network are still being reported at a rate of 6.6 TFs and 35 PDIs per year (Carrasco Pro et al, 2018). More importantly, most PDIs reported in the literature correspond to highly studied TFs and cytokines.…”

Section: Introductionmentioning

confidence: 99%

Comprehensive mapping of the human cytokine gene regulatory network

Santoso¹,

Lal

et al. 2020

Preprint

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Proper cytokine gene expression is essential in development, homeostasis, and immune responses. Studies on the transcriptional control of cytokine genes have mostly focused on highly researched transcription factors (TFs) and cytokines, resulting in an incomplete portrait of cytokine gene regulation. Here, we use enhanced yeast one-hybrid (eY1H) assays to derive a comprehensive network comprising 1,380 interactions between 265TFs and 108 cytokine gene promoters, greatly expanding the known repertoire of TFcytokine gene interactions. We found an enrichment of nuclear receptors and confirmed their role in cytokine regulation in primary macrophages. Additionally, we used the eY1Hderived network as a framework to identify pairs of TFs that synergistically modulate cytokine gene expression, and to identify novel TF-cytokine regulatory axes in immune diseases and immune cell lineage development. Overall, the eY1H data provides a rich resource to study cytokine regulation in a variety of physiological and disease contexts. 8 High Fidelity (ThermoFisher) from a pool of human genomic DNA (Clonetech). PCR products were Gateway cloned into the pDONR P1-P4 vector and entry clones were confirmed by Sanger sequencing. Then DNA-baits were Gateway cloned upstream of two reporter genes (HIS3 and LacZ) and both reporter constructs were integrated into the yeast genome to generate chromatinized DNA-bait strains (Deplancke et al., 2006a;Deplancke et al., 2006b). Yeast DNA-bait strains were confirmed by Sanger sequencing.DNA-bait strains were mated with an array of 1,086 TF-prey yeast strains expressing human TFs fused to the yeast Gal4 activation domain (AD) (Fuxman Bass et al., 2015).Matings were performed using a Singer Rotor robotic platform that manipulates yeast strains in a 1,536-colony format. An interaction was detected when a TF-prey binds the DNA-bait and the AD moiety activates reporter gene expression, allowing the mated yeast to grow on media lacking histidine, overcome the addition of 3-amino-triazole (3AT), a competitive inhibitor of the His3p enzyme, and convert the colorless X-gal into a blue compound. Each interaction was tested in quadruplicate and interactions were considered positive if at least two of the four mated colonies tested positively (>90% of detected interactions tested positively for all four colonies).Images of mated colonies on plates lacking histidine and containing 3AT and Xgal were processed using the Mybrid web-tool to detect positive interactions (Reece-Hoyes et al., 2013). Positive interactions detected by Mybrid were then manually checked and curated. False positives detected by Mybrid, which typically occur on plates with uneven background, were removed. False negatives missed by Mybrid, which typically occur when baits exhibit high background reporter gene expression or when interactions occur next to very strong positives, were included. A total of high-quality 1,380 PDIs 9 between 265 TFs and 108 cytokine promoters were included in the final dataset (Table S3). The eY1H interactions...

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“…we suspected that under conditions of GGTase inhibition, expression of a transcription factor necessary for IL-10 may be compromised. To test this, we performed RNA-sequencing on TLR9- have been shown to regulate IL-10 expression in other cell types ( Figure 5B-D, Supplementary Figure 7C), either through activation or repression (defined in 30 ). We decided to focus on BLIMP1 for two reasons.…”

mentioning

confidence: 99%

Cholesterol metabolism drives regulatory B cell function

Bibby

Purvis

Hayday

et al. 2020

Preprint

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Regulatory B cells restrict immune and inflammatory responses across a number of contexts. Thiscapacity is mediated primarily through the production of IL-10. Here we demonstrate that the induction of a regulatory program in human B cells is dependent on a metabolic priming event driven 25 by cholesterol metabolism. Synthesis of the metabolic intermediate geranylgeranyl pyrophosphate (GGPP) was required to specifically drive IL-10 production, and to attenuate Th1 responses.Furthermore, GGPP-dependent protein modifications controlled signaling through PI3Kd-AKT-GSK3, which in turn promoted BLIMP1-dependent IL-10 production. Inherited gene mutations in cholesterol metabolism result in a severe autoinflammatory syndrome, termed mevalonate kinase 30 deficiency (MKD). Consistent with our findings, B cells from MKD patients induced poor IL-10 responses and were functionally impaired. Moreover, metabolic supplementation with GGPP was able to reverse this defect. Collectively, our data define cholesterol metabolism as an integral metabolic pathway for the optimal functioning of human IL-10 producing regulatory B cells. 40Comparable suppressive activity has been demonstrated in human regulatory B cells in vitro, suggesting that these cells also contribute toward regulating inflammatory responses in humans 5,6 . In support of this, IL-10 producing B cells have been demonstrated to be numerically depleted or functional impaired, ex vivo, in patients with inflammatory disease 5,11,12 . 45Despite the importance of IL-10 production by B cells, relatively little is known about the molecular mechanisms that govern its expression. Typically, induction of a regulatory phenotype in both human and murine B cells has been achieved through ligation of TLR9 or CD40 5,6,13 . Downstream, PI3K and ERK signals appear to be important for IL-10 expression 14,15 . This is in broad agreement with in vivo data from mouse models suggesting that both TLR and CD40 signals are required for the induction of 50 IL-10 in response to inflammatory stimuli 3,13 . However, precise details of the signaling cascades or cellular profiles underpinning the induction of a regulatory program in B cells are poorly understood.Control of immune cell metabolism is critical in regulating fundamental immunological processes 16,17 . However, in comparison to innate cell and T cell lineages, there has been relatively little work 55 aimed at understanding the metabolic regulation of B cell biology [18][19][20] . Furthermore, there is currently no understanding toward the metabolic requirements of regulatory B cells. An emerging concept from studies of regulatory T cells and M2 macrophages is their heightened reliance on lipid metabolism in comparison to the metabolic requirements of inflammatory immune cell lineages. Much of this work has focused on fatty acid oxidation, defining this as a central pathway that underpins polarization and 60 effector functions in regulatory cells 21 . In contrast, the contribution of cholesterol metabolism (the multi-step conversion of HM...

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Global landscape of mouse and human cytokine transcriptional regulation

Cited by 47 publications

References 81 publications

Comparative transcriptome analysis reveals the intensive early-stage responses of host cells to SARS-CoV-2 infection

Comparative transcriptome analysis reveals the intensive early-stage responses of host cells to SARS-CoV-2 infection

Comprehensive mapping of the human cytokine gene regulatory network

Cholesterol metabolism drives regulatory B cell function

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