Remodeling of the actin cytoskeleton through actin dynamics (assembly and disassembly of filamentous actin) is known to be essential for numerous basic biological processes. In addition, recent in vitro studies provided evidence that actin dynamics participate in the control of gene expression. A spontaneous mouse mutant, corneal disease 1 (corn1), is deficient for a regulator of actin dynamics, destrin (DSTN; also known as actin depolymerizing factor or ADF), and develops epithelial hyperproliferation and neovascularization in the cornea. Dstncorn1 mice exhibit the actin dynamics defect in the corneal epithelial cells as evidenced by increased filamentous actin, offering an in vivo model to investigate the physiological significance of the transcriptional regulation by actin dynamics. To examine the effect of the Dstncorn1 mutation on gene expression, we performed a microarray analysis using the cornea from Dstncorn1 and wild-type control mice. A dramatic alteration of gene expression was observed in the Dstncorn1 cornea, with 1,226 annotated genes differentially expressed. Functional annotation of these genes revealed that most significantly enriched functional categories are associated with actin and/or cytoskeleton. Among genes that belong to these categories, a considerable number of serum response factor (SRF) target genes were found, indicating the existence of the actin-SRF pathway of transcriptional regulation in vivo. A comparative study using an allelic mutant strain, Dstncorn1-2J, with milder corneal phenotypes also suggested that the severity of the actin dynamics defect correlates with the level of gene expression changes. Our study provides evidence that actin dynamics have a strong impact on gene expression in vivo.
Effect of destrin mutations on the gene expression profile in vivo.
Sex, Age
View SamplesThe purpose of this study is to characterize gene expression changes that occur when conditional knock-out of Srf rescues mutant phenotypes in the cornea of Dstncorn1 mice.
Serum response factor: positive and negative regulation of an epithelial gene expression network in the destrin mutant cornea.
Specimen part
View SampleshEPI-NCSC are neural crest derived multipotent somatic stem cells that persist in hair follicle stem cell niche, termed the bulge, and persist into adulthood (Clewes O et al, 2011). The purpose of this project was to generate two gene expression profiles, (1) of ex vivo expanded hEPI-NCSC (XP) and (2) of cells, whihc after expansion were grown in a culture medium (NP1), which was empirically designed to pre-differentiate the multipotent stem cells into neural stemcell like cells.
Differentiation of human epidermal neural crest stem cells (hEPI-NCSC) into virtually homogenous populations of dopaminergic neurons.
Sex, Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Brown Adipose YY1 Deficiency Activates Expression of Secreted Proteins Linked to Energy Expenditure and Prevents Diet-Induced Obesity.
Age, Specimen part, Treatment
View SamplesAnalysis of brown adipose tissue from Yin Yang 1 (YY1) brown fat specific knockout mice fed a high fat diet for 3 months. YY1 deficiency in brown adipose tissue leads to strong thermogenic deficiency. The goal was to identify the genes controlled by YY1 responsible of brown fat defective function.
Brown Adipose YY1 Deficiency Activates Expression of Secreted Proteins Linked to Energy Expenditure and Prevents Diet-Induced Obesity.
Age, Specimen part, Treatment
View SamplesAnalysis of visceral white adipose tissue (EWAT) from Yin Yang 1 adipose-specific knockout mice exposed to cold (4C) for 4 days.
Brown Adipose YY1 Deficiency Activates Expression of Secreted Proteins Linked to Energy Expenditure and Prevents Diet-Induced Obesity.
Age, Specimen part, Treatment
View SamplesAnalysis of subcutaneous adipose tissue (IWAT) from Yin Yang 1 brown fat specific knockout mice fed a high fat diet for 2 weeks. The goal was to identify a gene signature of IWAT browning in YY1 mutant mice.
Brown Adipose YY1 Deficiency Activates Expression of Secreted Proteins Linked to Energy Expenditure and Prevents Diet-Induced Obesity.
Age, Specimen part, Treatment
View SamplesInterleukin-6 (IL-6) is an important growth factor for estrogen receptor-alpha (ER) positive breast cancer, and elevated serum IL-6 is associated with poor prognosis. We firstly demonstrated that pSTAT3 is the primary downstream IL-6 signaling pathway in ER-positive breast cancer, using ten different breast cancer cell lines. Three-dimensional cultures of these cell lines were also used to develop a 17-gene IL-6 specific gene signature that could be used to identify IL-6 driven disease. This signature included a variety of genes involved in immune cell function and migration, cell growth and apoptosis, and the tumor microenvironment. To further validate this IL-6 signature, we obtained 36 human ER-positive breast cancer tumor samples with matched serum for gene expression profiling and determination of an IL-6 pathway activation score (PAS). Patients with high IL-6 PAS were also enriched for elevated serum IL-6 (>=10 pg/ml). We then utilized a murine MCF-7 xenograft model to determine the role of IL-6 in ER-positive breast cancer and potential anti-IL-6 therapy in vivo. When IL-6 was administered in vivo, MCF-7 cells engrafted without the need for estrogen supplementation. Subsequently, we prophylactically treated mice at MCF-7 engraftment with an anti-IL-6 antibody (siltuximab), fulvestrant or combination therapy. Siltuximab alone was able to blunt MCF-7 engraftment. Similarly, when tumors were allowed to grow to 125 mm3 before treatment, siltuximab alone demonstrated tumor regressions in 90% (9/10) of tumors. Given the established role for IL-6 in ER+ breast cancer, this data demonstrates the potential for anti-IL-6 therapeutics.
Interleukin-6 is a potential therapeutic target in interleukin-6 dependent, estrogen receptor-α-positive breast cancer.
Specimen part
View SamplesAlthough recent studies support regenerative potential based on cardiac progenitor cells (CPCs), it remains unclear what cues regulate CPC fate. Using 2- and 3D-culture models, we demonstrate that the two most abundantly expressed matrix proteins in the heart, laminin and fibronectin, have opposite roles in CPC fate decision. CPCs on fibronectin showed predominantly nuclear localization of the transcriptional co-activator YAP and maintained proliferation. In contrast, seeding on laminin induced cytosolic retention and degradation of YAP and altered gene expression, which preceded decreased proliferation and enhanced lineage commitment. RNA-sequencing identified Plk2 as candidate target gene of YAP. Plk2 expression depended on YAP stability, was rapidly downregulated on laminin, and its regulation was sufficient to rescue and/or mimic the CPC response to laminin and fibronectin, respectively. These findings propose a novel role of Plk2 and identify an early molecular mechanism in matrix-instructed CPC fate with potential implications for therapeutic cardiac regeneration. Overall design: Expression profiling of cardiac progenitor cells in suspension and cultured on dishes coated with laminin or fibronectin or on non-coated dishes (biological triplicates each)
Polo-Like Kinase 2 is Dynamically Regulated to Coordinate Proliferation and Early Lineage Specification Downstream of Yes-Associated Protein 1 in Cardiac Progenitor Cells.
No sample metadata fields
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Active STAT5 regulates T-bet and eomesodermin expression in CD8 T cells and imprints a T-bet-dependent Tc1 program with repressed IL-6/TGF-β1 signaling.
Specimen part
View Samples