Background: Strategies to improve long term renal allograft survival have been directed to recipient dependent mechanisms of renal allograft injury. In contrast, no such efforts have been made to optimize organ quality in the donor. In order to get insight into the deleterious gene pathways expressed at different time points during deceased kidney transplantation, transcriptomics was performed on kidney biopsies from a large cohort of deceased kidney transplants.
Hypoxia and Complement-and-Coagulation Pathways in the Deceased Organ Donor as the Major Target for Intervention to Improve Renal Allograft Outcome.
Specimen part
View SamplesTumor metastasis and lack of NKG2D ligand (NKG2DL) expression are associated with poor prognosis in patients with colon cancer. Here we found that spironolactone (SPIR), an FDA-approved diuretic drug with a long-term safety profile, can upregulate NKG2DL expression in multiple colon cancer cell lines by activating the ATM-Chk2-mediated checkpoint pathway, which in turn enhances tumor elimination by natural killer cells. SPIR can also upregulate the expression of metastasis-suppressor genes TIMP2 and TIMP3, thereby reducing tumor cell invasiveness. Although SPIR is an aldosterone antagonist, its anti-tumor effects are independent of the mineralocorticoid receptor pathway. Instead, by screening the human nuclear hormone receptor siRNA library, we identify retinoid X receptor gamma (RXR gamma) as being indispensable for the anti-tumor functions of SPIR. Collectively, our results strongly support the use of SPIR or other RXR gamma-agonists with minimal side effects for colon cancer prevention and therapy.
Modulation of NKG2D ligand expression and metastasis in tumors by spironolactone via RXRγ activation.
Treatment
View SamplesWe have employed whole genome microarray expression profiling to identify genes differentially expressed in cord blood purified neutrophils after a short-term exposure to peptidoglycan (PGN).
Expression profile of cord blood neutrophils and dysregulation of HSPA1A and OLR1 upon challenge by bacterial peptidoglycan.
Specimen part, Treatment
View SamplesThymocyte selection-associated high mobility group box protein family member 2 (TOX2) is a transcription factor belonging to the TOX family that shares a highly conserved high mobility group DNA binding domain with the other TOX members. While TOX1 has been shown to be an essential regulator of T-cell and natural killer (NK) cell differentiation in mice, little is known about the roles of the other TOX family members in lymphocyte development, particularly in humans. In this study, we found that TOX2 was preferentially expressed in mature human NK cells and was upregulated during in vitro differentiation of NK cells from human umbilical cord blood (UCB)derived CD34+ cells. Gene silencing of TOX2 intrinsically hindered the transition between early developmental stages of NK cells, while overexpression of TOX2 enhanced the development of mature NK cells from UCB CD34+ cells. We subsequently found that TOX2 was independent of ETS-1 but could directly upregulate the transcription of TBX21 (encoding T-BET). Overexpression of T-BET rescued the TOX2 knockdown phenotypes. Given the essential function of T-BET in NK cell differentiation, TOX2 therefore plays a crucial role in controlling normal NK cell development by acting upstream of TBX21 transcriptional regulation.
TOX2 regulates human natural killer cell development by controlling T-BET expression.
Specimen part, Subject
View SamplesEye development and photoreceptor maintenance requires the retinal pigment epithelium (RPE), a thin layer of cells that underlies the neural retina. Despite its importance, RPE development has not been studied by a genomic approach. A microarray expression profiling methodology was established in this study for studying RPE development. The intact retina with RPE attached was dissected from developing embryos, and differentially expressed genes in RPE were inferred by comparing the dissected tissues with retinas without RPE using microarray and statistical analyses. We found 8810 probesets to be significantly expressed in RPE at 52 hours post-fertilization (hpf), of which 1443 might have biologically meaningful expression levels. Further, 78 and 988 probesets were found to be significantly over- or under-expressed in RPE respectively compared to retina. Also, 79.2% (38/48) of the known over-expressed probesets have been independently validated as RPE-related transcripts. The results strongly suggest that this methodology can obtain in vivo RPE specific gene expression from the zebrafish embryos and identify novel RPE markers.
Gene expression profiling of zebrafish embryonic retinal pigment epithelium in vivo.
Specimen part
View SamplesRetinal cells are specified in a zebrafish recessive mutant called young (yng) but they fail to terminally differentiate; i.e. extend neurites and make synaptic contacts. A point mutation in a brahma-related gene 1 (brg1) is responsible for this phenotype. In this microarray study, a three-factor factorial design was utilized to investigate the effects of 1) mutation, 2) change in time (36 vs. 52hpf), and 3) change in tissue (retina vs. whole embryos), and their interactions on gene expression. Significant probesets were inferred by using both specific contrasts of the fitted Analysis of Variance (ANOVA) models and a corresponding 2-fold expression cutoff. The probesets were grouped into three broad categories: 1) Brg1-regulated retinal differentiation genes (731 probsets), 2) Retinal specific genes but independent of Brg1 regulation (3038 probesets) and 3) Genes regulated by Brg1 but outside the retina (107 probesets). Four gene groups/pathways including neurite outgrowth regulators, Delta-Notch signalling molecules, Irx family members and specific cell cycle regulators were identified in the first group, and their relevance for retinal differentiation functionally validated. This study demonstrates that an approach such as ours can identify relevant genes and pathways involved in retinal development as well as the development of other tissues at the same time.
Factorial microarray analysis of zebrafish retinal development.
Specimen part
View SamplesMost metabolic studies are conducted in male animals; thus, the molecular mechanism controlling gender-specific pathways has been neglected, including sex-dependent responses to peroxisome proliferator-activated receptors (PPARs). Here we show that PPARalpha has broad female-dependent repressive actions on hepatic genes involved in steroid metabolism and inflammation. In males, this effect is reproduced by the administration of synthetic PPARalpha ligand. Using the steroid hydroxylase gene Cyp7b1 as a model, we elucidated the molecular mechanism of this PPARalpha-dependent repression. Initial sumoylation of the ligand-binding domain of PPARalpha triggers the interaction of PPARalpha with the GA-binding protein alpha bound to the target promoter. Histone deacetylase is then recruited, and histones and adjacent Sp1-binding site are methylated. These events result in the loss of Sp1-stimulated expression, and thus the down-regulation of Cyp7b1. Physiologically, this repression confers protection against estrogen-induced intrahepatic cholestasis, paving the way for a novel therapy against the most common hepatic disease during pregnancy.
Sumoylated PPARalpha mediates sex-specific gene repression and protects the liver from estrogen-induced toxicity in mice.
No sample metadata fields
View SamplesWe used microarrays to compare gene expression profiles between mouse mammary tumors initiated by Myc to those that have escaped Myc oncogene dependence.
Heterogeneity in MYC-induced mammary tumors contributes to escape from oncogene dependence.
Specimen part
View SamplesWe compared PBMC genomic response to exercise in both early (EB) and late-pubertal boys (LB)
Brief bout of exercise alters gene expression in peripheral blood mononuclear cells of early- and late-pubertal males.
No sample metadata fields
View SamplesWe compared PBMC genomic response to exercise in both early (EG) and late-pubertal girls (LG)
A brief bout of exercise alters gene expression and distinct gene pathways in peripheral blood mononuclear cells of early- and late-pubertal females.
No sample metadata fields
View Samples