The Reactome Pathway Knowledgebase

Fabregat, Antonio; Jupe, S; Matthews, Lisa; Sidiropoulos, Konstantinos; Gillespie, Marc; Garapati, Phani; Haw, Robin; Jassal, Bijay; Korninger, Florian; May, Bruce; Milacic, Marija; Roca, Corina Duenas; Rothfels, Karen; Sevilla, Cristoffer; Shamovsky, Veronica; Shorser, Solomon; Varusai, Thawfeek; Viteri, Guilherme; Weiser, Joel; Wu, Guanming; Stein, Lincoln; Hermjakob, Henning; D’Eustachio, Peter

doi:10.1093/nar/gkx1132

Cited by 2,549 publications

(2,058 citation statements)

References 11 publications

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“…Same gene lists were used to identify gene set enrichment analysis as described in enrichr [22]. Results of Reactome pathway term [23] output for the up- or down-regulated genes sorted based on P values <0.01 are indicated as bar graphs.…”

Section: Methodsmentioning

confidence: 99%

PRMT5 inhibition promotes osteogenic differentiation of mesenchymal stromal cells and represses basal interferon stimulated gene expression

Kota

Roening

Patel

et al. 2018

Bone

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Protein arginine methyltransferases (PRMTs) catalyze symmetric and asymmetric methylation on arginine residues of multiple protein targets including histones and have essential roles in organismal development and disease. PRMT5 mediates symmetric di-methylation (sDMA) of arginine 2 (H3R2me2s) and arginine 8 on histone 3 (H3R8me2s), arginine 3 on histones 2A and 4 (H2A/H4R3me2s) as well as several non-histone substrates like Sm proteins. Here, we found that selective inhibition of PRMT5 in mesenchymal stromal cells (MSCs) led to a reduction in colony forming units (CFUs) and increased osteoblast differentiation. PRMT5 inhibition blocked global symmetric dimethylation of H3R8 and H4R3 but not on H3R2. Genome-wide expression analysis by total RNA sequencing of mesenchymal stromal cells undergoing osteogenic differentiation revealed significant reduction in the intrinsic expression of several interferon-stimulated genes (ISGs) upon PRMT5 inhibition. Effects of PRMT5 inhibition on basal ISG expression and osteogenic differentiation was effectively blocked by exogenous activation of type I IFN signaling. Together, these results indicate important functions for PRMT5 in the regulation of basal interferon gene expression in MSCs and in the control of differentiation potential of MSCs during osteogenic differentiation.

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Section: Methodsmentioning

confidence: 99%

PRMT5 inhibition promotes osteogenic differentiation of mesenchymal stromal cells and represses basal interferon stimulated gene expression

Kota

Roening

Patel

et al. 2018

Bone

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“…The altered microbiome is associated with gut wall inflammation, breakdown of tight junctions, decreased production of short-chain fatty acids (an important nutrient source for enterocytes), and generation of gut-derived uremic toxins such as indoxyl sulphate and p-cresyl sulphate. These uremic toxins translocate into the bloodstream and induce systemic effects as outlined in Figure 1 (image credit of enterocyte, lymphocyte, and bacteria from Reactome project [133]). …”

Section: Breakdown Of the Gut-epithelial Barrier And Systemic Translomentioning

confidence: 99%

Altered microbiome in chronic kidney disease: systemic effects of gut-derived uremic toxins

et al. 2018

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In chronic kidney disease (CKD), influx of urea and other retained toxins exerts a change in the gut microbiome. There is decreased number of beneficial bacteria that produce short-chain fatty acids, an essential nutrient for the colonic epithelium, concurrent with an increase in bacteria that produce uremic toxins such as indoxyl sulphate, p-cresyl sulphate, and trimethylamine-N-oxide (TMAO). Due to intestinal wall inflammation and degradation of intercellular tight junctions, gut-derived uremic toxins translocate into the bloodstream and exert systemic effects. In this review, we discuss the evidence supporting a role for gut-derived uremic toxins in promoting multiorgan dysfunction via inflammatory, oxidative stress, and apoptosis pathways. End-organ effects include vascular calcification, kidney fibrosis, anemia, impaired immune system, adipocyte dysfunction with insulin resistance, and low turnover bone disease. Higher blood levels of gut-derived uremic toxins are associated with increased cardiovascular events and mortality in the CKD population. Clinical trials that have examined interventions to trap toxic products or reverse gut microbial dysbiosis via oral activated charcoal AST-120, prebiotics and probiotics have not shown impact on cardiovascular or survival outcomes but were limited by sample size and short trials. In summary, the gut microbiome is a major contributor to adverse cardiovascular outcomes and progression of CKD.

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“…Based on these studies databases such as STRING 18 and REACTOME 19 show UTX at the center of a very complex interaction network with established or predicted interactions. Based on these studies databases such as STRING 18 and REACTOME 19 show UTX at the center of a very complex interaction network with established or predicted interactions.…”

Section: Protein Interactionsmentioning

confidence: 99%

The histone demethylase UTX/KDM6A in cancer: Progress and puzzles

Schulz

Lang

Koch

et al. 2019

Intl Journal of Cancer

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The lysine‐specific demethylase 6A/UTX (gene name KDM6A) acts as a component of the COMPASS complex to control gene activation. UTX demethylates H3K27me2/3 at genes and enhancers. Deleterious mutations in KDM6A are found in many cancer types, prominently urothelial carcinoma and certain T‐cell leukemias. In certain cancers, however, UTX supports oncogenic transcription factors, e.g. steroid hormone receptors in breast and prostate cancer. In fetal development, UTX regulates lineage choice and cell differentiation. Analogously, loss of UTX function in cancer may lead to metaplasia or impede differentiation. Likely because its function is contingent on its interacting transcription factors, the effects of UTX inactivation are not uniform and require detailed investigation in each cancer type. In urothelial carcinoma, in particular, the functional consequences of the frequent mutations in KDM6A and other COMPASS component genes are poorly understood. Nevertheless, UTX inactivation appears to sensitize many cancers to inhibitors of the H3K27 methyltransferase EZH2. Conversely, inhibitors of UTX enzymatic activity may be applicable in cancers with an oncogenic UTX function. Intriguingly, the fact that KDM6A is localized on the X‐chromosome, but both copies are expressed, may account for gender‐specific differences in cancer susceptibility. In conclusion, despite recent progress, many open questions need to be addressed, most importantly, the detailed mechanisms by which KDM6A inactivation promotes various cancers, but also with which proteins UTX interacts in and apart from the COMPASS complex, and to which extent its catalytic function is required for its tumor‐suppressive function.

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The Reactome Pathway Knowledgebase

Cited by 2,549 publications

References 11 publications

PRMT5 inhibition promotes osteogenic differentiation of mesenchymal stromal cells and represses basal interferon stimulated gene expression

PRMT5 inhibition promotes osteogenic differentiation of mesenchymal stromal cells and represses basal interferon stimulated gene expression

Altered microbiome in chronic kidney disease: systemic effects of gut-derived uremic toxins

The histone demethylase UTX/KDM6A in cancer: Progress and puzzles

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