Project description:Goal of the experiment: To identify and understand the overall transcriptional programming of human colorectal cancer tumors by evaluating gene expression profiles of tumors from four murine models, and comparing and contrasting these to the developing stages of the mouse embryonic colon. Experiment description: Colorectal cancer results from multiple genetic and epigenetic events that produce variable histologies and clinical outcomes. To identify gene regulatory programs that underlie colon tumorigenesis, we profiled gene expression in 39 mouse colon tumors from four independent mouse models and compared this to mouse colon embryonic development, as well as with 100 human colon carcinomas. Here, we report a striking recapitulation of embryonic patterns of gene expression in both mouse and human colon tumors. All four of the mouse colon tumor models exhibited large-scale activation of embryonic gene expression signatures. The two nuclear beta-catenin-positive mouse tumors (azoxymethane-treated [AOM] and ApcMin/+), exhibited strong activation of genes characteristic of those expressed in the earliest embryonic stages, while tumors from two other models (Smad3-/- and Tgfb1-/- x Rag2-/-) exhibited lower activation of early stage-specific genes but substantial expression of general embryonic colon genes. Human colon cancer cases over-expressed genes characteristic of both early and late embryonic stages. Examining tumor gene expression through the lens of development has revealed an extensive network of therapeutic targets for cancer control. Experiment Overall Design: Transcriptional signatures across human colorectal carcinomas and normal human colon tissue samples were evaluated by referencing all the samples to the median gene expression value across all the samples. A second complementary strategy compared the gene expression levels of the tumors to those of normal adult colon. Experiment Overall Design: Values were transformed from a log base 2 to linear values. Each measurement was divided by the 50.0th percentile of all measurements in that sample. Each gene was divided by the median of its measurements in all samples. If the median of the raw values was below 10 then each measurement for that gene was divided by 10 if the numerator was above 10, otherwise the measurement was thrown out.

Project description:Hayashi2013 - Extended TNF-induced Signaling with Gene Expression Dynamics (Model B) Tumor necrosis factor (TNF) plays a crucial role in inflammation and is associated with diseases such as rheumatoid arthritis and cancer. While TNF signaling pathways are well studied, targeted regulation of proinflammatory responses remains a challenge. In this study, Hayashi et al., (2013) developed a computational model to simulate TNF-induced activation of MAP kinase (p38), NF-κB, and proinflammatory gene expression in murine fibroblast cells. The model parameters were optimized to fit experimental data, ensuring accurate representation of TNF signaling dynamics. The simulations using in silico knockouts identified receptor-interacting protein 1 (RIP1) as a key regulator of TNF-driven proinflammatory responses. Experimental validation using Necrostatin-1, a RIP1 inhibitor, confirmed these predictions and demonstrated its potential as a therapeutic target for regulating proinflammatory mediators in TNF-driven diseases. This model is described in the article: Hayashi K, Piras V, Tabata S, Tomita M, Selvarajoo K. A systems biology approach to suppress TNF-induced proinflammatory gene expressions. Cell Commun Signal. 2013 Nov 7;11:84. doi: 10.1186/1478-811X-11-84. PMID: 24199619; PMCID: PMC3832246. Abstract: Background: Tumor necrosis factor (TNF) is a widely studied cytokine (ligand) that induces proinflammatory signaling and regulates myriad cellular processes. In major illnesses, such as rheumatoid arthritis and certain cancers, the expression of TNF is elevated. Despite much progress in the field, the targeted regulation of TNF response for therapeutic benefits remains suboptimal. Here, to effectively regulate the proinflammatory response induced by TNF, a systems biology approach was adopted. Results: We developed a computational model to investigate the temporal activations of MAP kinase (p38), nuclear factor (NF)-κB, and the kinetics of 3 groups of genes, defined by early, intermediate and late phases, in murine embryonic fibroblast (MEF) and 3T3 cells. To identify a crucial target that suppresses, and not abolishes, proinflammatory genes, the model was tested in several in silico knock out (KO) conditions. Among the candidate molecules tested, in silico RIP1 KO effectively regulated all groups of proinflammatory genes (early, middle and late). To validate this result, we experimentally inhibited TNF signaling in MEF and 3T3 cells with RIP1 inhibitor, Necrostatin-1 (Nec-1), and investigated 10 genes (Il6, Nfkbia, Jun, Tnfaip3, Ccl7, Vcam1, Cxcl10, Mmp3, Mmp13, Enpp2) belonging to the 3 major groups of upregulated genes. As predicted by the model, all measured genes were significantly impaired. Conclusions: Our results demonstrate that Nec-1 modulates TNF-induced proinflammatory response, and may potentially be used as a therapeutic target for inflammatory diseases such as rheumatoid arthritis and osteoarthritis. Figure S3, obtained from the simulation of TNFR1 Model B, is highlighted here. This model was curated during the Hackathon hosted by BioMed X GmbH in 2024.

Project description:Hookworms are parasitic nematodes that chronically infect 170-440 million people, despite healthy human immune systems ending most infections quickly. How hookworms successfully overcome host resistance is unclear, but is thought to involve hookworm proteins that either digest host tissues or dampen the host's immune system. To find such proteins in the model hookworm Ancylostoma ceylanicum, we identified hookworm genes encoding proteins excreted into the environment, genes expressed in the intestine, and genes transcriptionally upregulated in response to a normal host immune system. To maximize our accuracy, we repredicted 33,190 protein-coding genes in A. ceylanicum with a BUSCO completeness of 95.3%. We collected excreted-secreted (ES) proteins from two sets of adult hookworms in vitro, and used mass spectrometry to identify 565 A. ceylanicum genes encoding ES proteins; we also used RNA-seq to identify A. ceylanicum genes expressed both in young adults (12 days post-infection) and in intestines and non-intestinal tissues dissected from mature adults (19 days post-infection), with hamster hosts that either had normal immune systems or were immunosuppressed by dexamethasone. In adult A. ceylanicum, we observed 2,145 and 1,694 genes with intestine- and non-intestine-biased expression, respectively. Comparing hookworm gene activity in normal versus immunosuppressed hosts, we observed essentially no changes of gene activity in non-blood-feeding 12-day young adults or non-intestinal 19-day adult tissues. However, in intestinal 19-day adult tissues, we observed 671 genes upregulated at least two-fold in normal hosts versus immunosuppressed hosts (positively immunoregulated), and 75 genes that were negatively immunoregulated; thus, immunoregulation was observed only in mature adult hookworm intestine, directly exposed to host blood. Of the positively immunoregulated intestinal genes, 590 (87.9%) showed male-biased gene expression (9.8-fold greater overlap than chance), suggesting that male and female hookworms have different responses to host immune systems; of the other 81 non-male-biased genes, 53 encoded ES proteins, a 38-fold greater overlap than expected by chance. Of these 53 immunoregulated ES genes, 26 had ES gene homologs in the closely related hookworm Ancylostoma caninum, five in the human hookworm Necator americanus, and four in the more distantly related strongylid parasite Haemonchus contortus. Such a mixture of rapidly evolving and conserved genes could serve as virulence factors enabling infection.

			Action	DRS
	20190611_humanuniprot_XAGE1B.fasta	Fasta
	20211117_ZS_WWT_xage1b_ty1PD_TMT10.msf	Msf
	20211117_ZS_WWT_xage1b_ty1PD_TMT10.msfView	Msf
	20211117_ZS_WWT_xage1b_ty1PD_TMT10.pdResult	Other
	20211117_ZS_WWT_xage1b_ty1PD_TMT10.pdResultView	Other

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XAGE1B is a transcriptional regulator that acts via liquid-liquid phase separation to promote lung adenocarcinoma oncogenesis

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