Discovering relationships between nuclear receptor signaling pathways, genes, and tissues in Transcriptomine

Becnel, Lauren B.; Ochsner, Scott A.; Darlington, Yolanda F.; McOwiti, Apollo; Kankanamge, Wasula H.; Dehart, Michael; Naumov, Alexey; McKenna, Neil J.

doi:10.1126/scisignal.aah6275

Cited by 38 publications

(28 citation statements)

References 128 publications

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“…The functional interactions between nuclear receptors (NRs) and cytokine genes were obtained from the literature-reported network and the Nuclear Receptor Signaling Atlas (NURSA) Transcriptomine resource (Becnel et al, 2017) on July 26, 2019 (Table S4).…”

Section: Nuclear Receptor Functional Interactionsmentioning

confidence: 99%

“…Indeed, NRs have been shown to modulate the expression of key cytokines, such as Il17a (Hermann-Kleiter et al, 2012;Ivanov et al, 2006) and TNF (Jiang et al, 1998), in immune cell differentiation and autoimmune disorders. To determine whether NRs identified by eY1H assays potentially regulate their target cytokine genes, we searched for functional evidence for the eY1H PDIs in the literature and in expression profiling datasets from the Nuclear Receptor Signaling Atlas (NURSA) Transcriptomine database (Becnel et al, 2017). Notably, for 80 of the 248 PDIs, the NR has been found to functionally regulate its target cytokine gene ( Figure 3B and Table S4); however, in most cases, direct DNA binding had not been reported.…”

Section: Role Of Nuclear Receptors In Modulating the Expression Of Cymentioning

confidence: 99%

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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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Section: Nuclear Receptor Functional Interactionsmentioning

confidence: 99%

Section: Role Of Nuclear Receptors In Modulating the Expression Of Cymentioning

confidence: 99%

Comprehensive mapping of the human cytokine gene regulatory network

Santoso¹,

Lal

et al. 2020

Preprint

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“…Similarly, the MetaSignature DataBase (59), which is based on multi-cohort transcriptome analysis of transcriptomic data from over 100 diseases, identifies "Respiratory Syncytial Virus", "Dengue", and "Meta-Virus" as top diseases with statistically significant and negative effect sizes with respect to RBM4. Furthermore, The Signaling Pathways Project (https://www.signalingpathways.org/index.jsf) lists the IFNg receptor family as a potent regulator of RBM4 expression (60). In our own previous work (32), we established that RBM4 is necessary for protein expression of ULBP1, an NKGD2 ligand that acts a signal for recognition of virally infected cells by NK cells.…”

Section: Discussionmentioning

confidence: 94%

Post-transcriptional regulation of human endogenous retroviruses by RNA-Binding Motif Protein 4, RBM4

Foroushani

Chim

Wong

et al. 2020

Preprint

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The human genome encodes for over 1,500 RNA-binding proteins (RBPs), which coordinate regulatory events on RNA transcripts (Gerstberger et al., 2014). Most studies of RBPs concentrate on their action on mRNAs that encode protein, which constitute a minority of the transcriptome. A widely neglected subset of our transcriptome derives from integrated retroviral elements termed endogenous retroviruses (ERVs) that comprise ~8% of the human genome. Some ERVs have been shown to be transcribed under physiological and pathological conditions suggesting that sophisticated regulatory mechanisms to coordinate and prevent their ectopic expression exist. However, it is unknown whether RBPs and ERV transcripts directly interact to provide a post-transcriptional layer of regulation. Here, we implemented a computational pipeline to determine the correlation of expression between individual RBPs and ERVs from single-cell or bulk RNA sequencing data. One of our top candidates for an RBP negatively regulating ERV expression was RNA-Binding Motif Protein 4 (RBM4). We used PAR-CLIP to demonstrate that RBM4 indeed bound ERV transcripts at CGG consensus elements. Loss of RBM4 resulted in elevated transcript level of bound ERVs of the HERV-K and -H families, as well as increased expression of HERV-K envelope protein. We pinpointed RBM4 regulation of HERV-K to a CGG-containing element that is conserved in the long terminal repeats (LTRs) of HERV-K-10 and -K-11, and validated the functionality of this site using reporter assays. In summary, we identified RBPs as potential regulators of ERV function and demonstrate a new role for RBM4 in controlling ERV expression.Significance StatementThe expression of endogenous retroviruses (ERVs) appears to have broad impact on human biology. Nevertheless, only a handful of transcriptional regulators of ERV expression are known and to our knowledge no RNA-binding proteins (RBPs) were yet implicated in positive or negative post-transcriptional regulation of ERVs. We implemented a computational pipeline that allowed us to identify RBPs that modulate ERV expression levels. Experimental validation of one of the prime candidates we identified, RBM4, showed that it indeed bound RNAs made from ERVs and negatively regulated the levels of those RNAs. We hereby identify a new layer of ERV regulation by RBPs.

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“…Our data identified TRAF6 as a gene specifically down-regulated when HIF-1β, and its homologue in Drosophila melanogaster, Tango, are depleted. Analysis, using Ominer [40,41], of public datasets for ChIP-seq revealed that several transcription factors occupy genomic regions within the TRAF6 promoter, including Basic Helix-Loop-Helix ones such as HIFs. Furthermore, analysis of publicly released datasets for HIF-1β ChIP-seq identified a specific binding site in the promoter region of TRAF6 in T47D breast cancer cells [26].…”

Section: Discussionmentioning

confidence: 99%

HIF-1β Positively Regulates NF-κB Activity via Direct Control of TRAF6

D'Ignazio

Shakir

Batie

et al. 2020

IJMS

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NF-κB signalling is crucial for cellular responses to inflammation but is also associated with the hypoxia response. NF-κB and hypoxia inducible factor (HIF) transcription factors possess an intense molecular crosstalk. Although it is known that HIF-1α modulates NF-κB transcriptional response, very little is understood regarding how HIF-1β contributes to NF-κB signalling. Here, we demonstrate that HIF-1β is required for full NF-κB activation in cells following canonical and non-canonical stimuli. We found that HIF-1β specifically controls TRAF6 expression in human cells but also in Drosophila melanogaster. HIF-1β binds to the TRAF6 gene and controls its expression independently of HIF-1α. Furthermore, exogenous TRAF6 expression is able to rescue all of the cellular phenotypes observed in the absence of HIF-1β. These results indicate that HIF-1β is an important regulator of NF-κB with consequences for homeostasis and human disease.

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Discovering relationships between nuclear receptor signaling pathways, genes, and tissues in Transcriptomine

Cited by 38 publications

References 128 publications

Comprehensive mapping of the human cytokine gene regulatory network

Comprehensive mapping of the human cytokine gene regulatory network

Post-transcriptional regulation of human endogenous retroviruses by RNA-Binding Motif Protein 4, RBM4

HIF-1β Positively Regulates NF-κB Activity via Direct Control of TRAF6

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