Genetic Predisposition to Hepatocarcinogenesis in Inbred and Outbred Mouse Lines Selected for High or Low Inflammatory Response

AIRmax and AIRmin mouse strains phenotypically selected for high and low acute inflammatory responsiveness (AIR) are, respectively, susceptible or resistant to developing hepatocellular carcinoma (HCC) induced by the chemical carcinogens urethane and diethylnitrosamine (DEN). Early production of TNF-α, IL-1β, and IL-6 in the liver after DEN treatment correlated with tumor development in AIRmax mice. Transcriptome analysis of livers from untreated AIRmax and AIRmin mice showed specific gene expression profiles in each line, which might play a role in their differential susceptibility to HCC. Linkage analysis with SNP markers in F2 (AIRmax×AIRmin) intercross mice revealed two quantitative trait loci (QTL) in chromosomes 2 and 9, which are significantly associated with the number and progression of urethane-induced liver tumors. An independent linkage analysis with an intercross population from A/J and C57BL/6J inbred mice mapped regions in chromosomes 1 and 7 associated with the progression of urethane-induced liver tumors, evidencing the heterogeneity of HCC genetic control.

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Faculty Opinions recommendation of Ketamine and Imipramine Reverse Transcriptional Signatures of Susceptibility and Induce Resilience-Specific Gene Expression Profiles.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726695455.793533096 ◽

2017 ◽

Author(s):

E Ronald de Kloet ◽

Lisa van Weert ◽

Onno Meijer

Keyword(s):

Gene Expression ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Specific Gene ◽

Specific Gene Expression

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YAP Regulates the Expression ofHoxa1andHoxc13in Mouse and Human Oral and Skin Epithelial Tissues

Molecular and Cellular Biology ◽

10.1128/mcb.00765-14 ◽

2015 ◽

Vol 35 (8) ◽

pp. 1449-1461 ◽

Cited By ~ 18

Author(s):

Ming Liu ◽

Shuangyun Zhao ◽

Qingjie Lin ◽

Xiu-Ping Wang

Keyword(s):

Cell Proliferation ◽

Expression Profiles ◽

Tumor Development ◽

Gene Expression Profiles ◽

Tooth Germ ◽

Conditional Knockout ◽

Hippo Signaling ◽

Embryonic Mouse ◽

Downstream Targets ◽

Epithelial Tissues

Yes-associated protein (YAP) is a Hippo signaling transcriptional coactivator that plays pivotal roles in stem cell proliferation, organ size control, and tumor development. The downstream targets of YAP have been shown to be highly context dependent. In this study, we used the embryonic mouse tooth germ as a tool to search for the downstream targets of YAP in ectoderm-derived tissues.Yapdeficiency in the dental epithelium resulted in a small tooth germ with reduced epithelial cell proliferation. We compared the gene expression profiles of embryonic day 14.5 (E14.5)Yapconditional knockout andYAPtransgenic mouse tooth germs using transcriptome sequencing (RNA-Seq) and further confirmed the differentially expressed genes using real-time PCR andin situhybridization. We found that YAP regulates the expression ofHoxa1andHoxc13in oral and dental epithelial tissues as well as in the epidermis of skin during embryonic and adult stages. Sphere formation assay suggested thatHoxa1andHoxc13are functionally involved in YAP-regulated epithelial progenitor cell proliferation, and chromatin immunoprecipitation (ChIP) assay implies that YAP may regulateHoxa1andHoxc13expression through TEAD transcription factors. These results provide mechanistic insights into abnormal YAP activities in mice and humans.

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Convergent evolution of venom gland transcriptomes across Metazoa

10.1101/2021.07.04.451048 ◽

2021 ◽

Author(s):

Giulia Zancolli ◽

Maarten Reijnders ◽

Robert Waterhouse ◽

Marc Robinson-Rechavi

Keyword(s):

Gene Expression ◽

Regulatory Networks ◽

Molecular Mechanisms ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Venom Gland ◽

Bioactive Molecules ◽

Specific Gene ◽

Animal Kingdom ◽

Venom Glands

Animals have repeatedly evolved specialized organs and anatomical structures to produce and deliver a cocktail of potent bioactive molecules to subdue prey or predators: venom. This makes it one of the most widespread convergent functions in the animal kingdom. Whether animals have adopted the same genetic toolkit to evolved venom systems is a fascinating question that still eludes us. Here, we performed the first comparative analysis of venom gland transcriptomes from 20 venomous species spanning the main Metazoan lineages, to test whether different animals have independently adopted similar molecular mechanisms to perform the same function. We found a strong convergence in gene expression profiles, with venom glands being more similar to each other than to any other tissue from the same species, and their differences closely mirroring the species phylogeny. Although venom glands secrete some of the fastest evolving molecules (toxins), their gene expression does not evolve faster than evolutionarily older tissues. We found 15 venom gland specific gene modules enriched in endoplasmic reticulum stress and unfolded protein response pathways, indicating that animals have independently adopted stress response mechanisms to cope with mass production of toxins. This, in turns, activates regulatory networks for epithelial development, cell turnover and maintenance which seem composed of both convergent and lineage-specific factors, possibly reflecting the different developmental origins of venom glands. This study represents the first step towards an understanding of the molecular mechanisms underlying the repeated evolution of one of the most successful adaptive traits in the animal kingdom.

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Abstract 268: Strain-specific Cardiac Fibroblast Response to Isoproterenol-induced Cardiac Fibrosis

Circulation Research ◽

10.1161/res.121.suppl_1.268 ◽

2017 ◽

Vol 121 (suppl_1) ◽

Author(s):

Shuin Park ◽

Sara Ranjbarvaziri ◽

Fides Lay ◽

Peng Zhao ◽

Aldons J Lusis ◽

...

Keyword(s):

Gene Expression ◽

Cardiac Fibrosis ◽

Cardiac Fibroblasts ◽

Expression Profiles ◽

Inbred Mouse ◽

Gene Expression Profiles ◽

Mouse Strains ◽

Sequencing Analysis ◽

Different Strains

Fibroblasts are a heterogeneous population of cells that function within the injury response mechanisms across various tissues. Despite their importance in pathophysiology, the effects of different genetic backgrounds on fibroblast contribution to the development of disease has yet to be addressed. It has previously been shown that mice in the Hybrid Mouse Diversity Panel, which consists of 110 inbred mouse strains, display a spectrum in severity of cardiac fibrosis in response to chronic treatment of isoproterenol (ISO). Here, we characterized cardiac fibroblasts (CFbs) from three different mouse strains (C57BL/6J, C3H/HeJ, and KK/HIJ) which exhibited varying degrees of fibrosis after ISO treatment. The select strains of mice underwent sham or ISO treatment via intraperitoneally-implanted osmotic pumps for 21 days. Masson’s Trichrome staining showed significant differences in fibrosis in response to ISO, with KK/HIJ mice demonstrating the highest levels, C3H/HeJ exhibiting milder levels, and C57BL/6J demonstrating little to no fibrosis. When CFbs were isolated and cultured from each strain, the cells demonstrated similar traits at the basal level but responded to ISO stimuli in a strain-specific manner. Likewise, CFbs demonstrated differential behavior and gene expression in vivo in response to ISO. ISO treatment caused CFbs to proliferate similarly across all strains, however, immunofluorescence staining showed differential levels of CFb activation. Additionally, RNA-sequencing analysis revealed unique gene expression profiles of all three strains upon ISO treatment. Our study depicts the phenotypic heterogeneity of CFbs across different strains of mice and our results suggest that ISO-induced cardiac fibrosis is a complex process that is independent of fibroblast proliferation and is mainly driven by the activation/inhibition of genes involved in pro-fibrotic pathways.

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Dimethyl fumarate induces ferroptosis and impairs NF-κB/STAT3 signaling in DLBCL

Blood ◽

10.1182/blood.2020009404 ◽

2021 ◽

Author(s):

Anja Schmitt ◽

Wendan Xu ◽

Philip Bucher ◽

Melanie Grimm ◽

Martina Konantz ◽

...

Keyword(s):

Cell Death ◽

B Cell ◽

Expression Profiles ◽

Therapeutic Option ◽

Gene Expression Profiles ◽

B Cell Lymphoma ◽

Dimethyl Fumarate ◽

Specific Gene ◽

Molecular Heterogeneity ◽

Stat3 Signaling

Despite the development of novel targeted drugs, the molecular heterogeneity of diffuse large B-cell lymphoma (DLBCL) still poses a major therapeutic challenge. DLBCL can be classified into at least two major subtypes, i.e. germinal center B-cell-like (GCB) and the aggressive activated B-cell-like (ABC) DLBCL, each characterized by specific gene expression profiles and mutation patterns. Here we demonstrate a broad anti-tumor effect of dimethyl fumarate (DMF) on both DLBCL subtypes, which is mediated by the induction of ferroptosis, a form of cell death driven by the peroxidation of phospholipids. Due to high expression of arachidonate 5-lipoxygenase in concert with low glutathione and glutathione peroxidase 4 levels, DMF induces lipid peroxidation and thus ferroptosis particularly in GCB DLBCL. In ABC DLBCL cells, which are addicted to NF-κB and STAT3 survival signaling, DMF treatment efficiently inhibits the activity of the IKK complex and JAK kinases. Interestingly, the BCL-2 specific BH3 mimetic ABT-199 and an inhibitor of ferroptosis suppressor protein 1 synergize with DMF in inducing cell death in DLBCL. Collectively, our findings identify the clinically approved drug DMF as a promising novel therapeutic option in the treatment of both GCB and ABC DLBCL.

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Biophysical Techniques for Target Validation and Drug Discovery in Transcription-Targeted Therapy

International Journal of Molecular Sciences ◽

10.3390/ijms21072301 ◽

2020 ◽

Vol 21 (7) ◽

pp. 2301 ◽

Cited By ~ 3

Author(s):

Mehdi Moustaqil ◽

Yann Gambin ◽

Emma Sierecki

Keyword(s):

Drug Discovery ◽

Therapeutic Strategy ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Attractive Alternative ◽

Specific Gene ◽

Pharmaceutical Companies ◽

Biochemical Activity ◽

Biophysical Techniques ◽

And Personalized Medicine

In the post-genome era, pathologies become associated with specific gene expression profiles and defined molecular lesions can be identified. The traditional therapeutic strategy is to block the identified aberrant biochemical activity. However, an attractive alternative could aim at antagonizing key transcriptional events underlying the pathogenesis, thereby blocking the consequences of a disorder, irrespective of the original biochemical nature. This approach, called transcription therapy, is now rendered possible by major advances in biophysical technologies. In the last two decades, techniques have evolved to become key components of drug discovery platforms, within pharmaceutical companies as well as academic laboratories. This review outlines the current biophysical strategies for transcription manipulation and provides examples of successful applications. It also provides insights into the future development of biophysical methods in drug discovery and personalized medicine.

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In Vivo mRNA Profiling of Uropathogenic Escherichia coli from Diverse Phylogroups Reveals Common and Group-Specific Gene Expression Profiles

mBio ◽

10.1128/mbio.01075-14 ◽

2014 ◽

Vol 5 (4) ◽

Cited By ~ 39

Author(s):

Piotr Bielecki ◽

Uthayakumar Muthukumarasamy ◽

Denitsa Eckweiler ◽

Agata Bielecka ◽

Sarah Pohl ◽

...

Keyword(s):

Gene Expression ◽

Escherichia Coli ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Specific Gene ◽

Content Type ◽

E Coli ◽

Human Host ◽

Tract Infections

ABSTRACTmRNA profiling of pathogens during the course of human infections gives detailed information on the expression levels of relevant genes that drive pathogenicity and adaptation and at the same time allows for the delineation of phylogenetic relatedness of pathogens that cause specific diseases. In this study, we used mRNA sequencing to acquire information on the expression ofEscherichia colipathogenicity genes during urinary tract infections (UTI) in humans and to assign the UTI-associatedE. coliisolates to different phylogenetic groups. Whereas thein vivogene expression profiles of the majority of genes were conserved among 21E. colistrains in the urine of elderly patients suffering from an acute UTI, the specific gene expression profiles of the flexible genomes was diverse and reflected phylogenetic relationships. Furthermore, genes transcribedin vivorelative to laboratory media included well-described virulence factors, small regulatory RNAs, as well as genes not previously linked to bacterial virulence. Knowledge on relevant transcriptional responses that drive pathogenicity and adaptation of isolates to the human host might lead to the introduction of a virulence typing strategy into clinical microbiology, potentially facilitating management and prevention of the disease.IMPORTANCEUrinary tract infections (UTI) are very common; at least half of all women experience UTI, most of which are caused by pathogenicEscherichia colistrains. In this study, we applied massive parallel cDNA sequencing (RNA-seq) to provide unbiased, deep, and accurate insight into the nature and the dimension of the uropathogenicE. coligene expression profile during an acute UTI within the human host. This work was undertaken to identify key players in physiological adaptation processes and, hence, potential targets for new infection prevention and therapy interventions specifically aimed at sabotaging bacterial adaptation to the human host.

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