oPOSSUM: integrated tools for analysis of regulatory motif over-representation

Sui, Shannan Ho; Fulton, Debra L.; Arenillas, David J.; Kwon, Andrew Tae-Jun; Wasserman, Wyeth W.

doi:10.1093/nar/gkm427

Cited by 153 publications

(139 citation statements)

References 31 publications

Supporting

Mentioning

139

Contrasting

Order By: Relevance

“…Presumably, the aggressive HMET pancreatic tumor cells gained via in vivo selection the capability to overexpress hypoxia inducible genes under normoxic conditions. The promoter sequence analysis of the gene cluster revealed a significant enrichment for the binding site of the transcription factor Sox9 (14). We then hypothesized that SOX9-dependent transcriptional regulation of hypoxiaassociated genes under normoxic conditions could be responsible for the aggressive biology of HMET-induced pancreatic cancer, and may therefore contribute to aggressive tumor stages of pancreatic cancer.…”

Section: Discussionmentioning

confidence: 96%

“…The expression values for the genes significant for a specific pair-wise comparison extracted from the linear model were converted to log fold change relative to the mean of all samples and clustered using the SOTA algorithm with a Pearson uncentered metric within the program suite MeV 4.0 (http://www.tm4.org/mev.html). The genes constituting a cluster were analyzed for enrichment of transcription factor binding sites with the program oPOS-SUM 2.0 using the recommended significance threshold of Zscore > 10.0 and Fisher P-value < 0.01 (14).…”

Section: Microarray Analysismentioning

confidence: 99%

See 1 more Smart Citation

Hypoxia-Independent Gene Expression Mediated by SOX9 Promotes Aggressive Pancreatic Tumor Biology

Čamaj

Jäckel

Krebs

et al. 2014

Molecular Cancer Research

View full text Add to dashboard Cite

Pancreatic cancer aggressiveness is characterized by its high capacity for local invasion, ability to promote angiogenesis, and potential to metastasize. Hypoxia is known to represent a crucial step in the development of aggressive malignant features of many human cancers. However, micrometastatic tumors are not typically subjected to hypoxic events during early stages of dissemination; therefore, it is unclear how these tumors are able to maintain their aggressive phenotype. Thus, the identification of regulators of hypoxia-related genes in aggressive/ metastatic tumors represents a fundamental step for the design of future therapies to treat pancreatic cancer. To this end, transcriptomic profiles were compared between the nonmetastatic pancreatic cancer cell line FG (LMET) and its angiogenic/metastatic derivate L3.6pl (HMET) under normoxic or hypoxic conditions. Cluster analysis revealed a number of transcripts that were induced by hypoxia in nonmetastatic cancer cells. Strikingly, this cluster was determined to be constitutively activated under normoxia in the metastatic cancer cells and could not be further induced by hypoxia. A subset of these transcripts were regulated by the transcription factor SOX9 in the aggressivemetastatic cells, but driven by hypoxia-inducible factor-1a (HIF-1a) in the parental nonmetastatic cell line. Moreover, these transcripts were enriched in cancer-related networks including: WNT, CXCR4, retinoic acid, and (FAK) focal adhesion kinase, gene PTK2 signaling pathways. In functional assays, inhibition of SOX9 expression in HMET cells led to increased apoptosis and reduced migration in vitro and a significant reduction in primary tumor growth, angiogenesis, and metastasis following orthotopic tumor cell injection. At the molecular level, the control of SOX9 expression was associated with changes in the methylation status of the SOX9 promoter. Finally, SOX9 upregulation was verified in a series of tumor specimens of patients with pancreatic carcinoma.

show abstract

Section: Discussionmentioning

confidence: 96%

Section: Microarray Analysismentioning

confidence: 99%

Hypoxia-Independent Gene Expression Mediated by SOX9 Promotes Aggressive Pancreatic Tumor Biology

Čamaj

Jäckel

Krebs

et al. 2014

Molecular Cancer Research

View full text Add to dashboard Cite

show abstract

“…Animal experimental procedures were approved by the Institutional Animal Care and Use Committee of Obihiro University (no. [18][19][20][21][22][23][24][25]. Twelve Holstein cows (3-7 yr of age) that had been ovariectomized 40 -50 days before the beginning of the experiment were maintained in a free-stall barn throughout the experimental period and had free access to food and water.…”

Section: Methodsmentioning

confidence: 99%

Actions and interactions of progesterone and estrogen on transcriptome profiles of the bovine endometrium

Shimizu

Krebs

Bauersachs

et al. 2010

Physiological Genomics

View full text Add to dashboard Cite

The aim of our study was to analyze endometrial gene expression profiles in ovariectomized cows treated with estradiol and/or progesterone by using microarray analysis. Clustering of differentially expressed genes allowed separation into distinct hormone response patterns. These patterns could be classified into independent and interdependent actions of the steroid hormones estrogen and progesterone. The use of ovariectomized cows and external administration of hormones identified a set of genes whose regulation depends on a progesterone priming effect. The progesterone-primed estrogen response comprises gene functions such as migration, cell differentiation, and cell adhesion and therefore may play a crucial role in tissue remodeling, as one of its key regulators in the endometrium, TGFB2, is among this group of progesterone-primed genes. Functional annotation analysis of the estrogen-responsive gene clusters shows a clear dominance of functions such as cell cycle, morphogenesis, and differentiation. The functional profile of the progesterone-responsive clusters is less clear but nevertheless shows some important fertility-related terms like luteinization, oocyte maturation, and catecholamine metabolism. We looked for putative regulators of the steroid hormone response in endometrium by searching for enriched transcription factor binding sites in the promoter regions of the genes with similar hormone response profile. This analysis identified transcription factors such as SP1, NFYA, FOXA2, IRF2, ESR1, and NOBOX as candidate regulators of gene expression in bovine endometrium treated with steroid hormones. Taken together, our data provide novel insights into the regulation of bovine endometrial physiology by steroid hormones.

show abstract

“…In silico transcription factor binding site analyses Transcription factor binding site (TFBS) enrichment analysis of vertebrate transcription factors was performed using the oPOSSUM single site analysis tool (Ho Sui et al, 2007). The following threshold criteria were used: a z-score at least 10 and a Fisher score at most 0.01.…”

Section: Identification Of Sdeg Genes and Pathway Analysismentioning

confidence: 99%

Loss of PPARγ in endothelial cells leads to impaired angiogenesis

Vattulainen-Collanus

Akinrinade

et al. 2016

Journal of Cell Science

View full text Add to dashboard Cite

Tie2-promoter-mediated loss of peroxisome proliferator-activated receptor gamma (PPARγ, also known as PPARG) in mice leads to osteopetrosis and pulmonary arterial hypertension. Vascular disease is associated with loss of PPARγ in pulmonary microvascular endothelial cells (PMVEC); we evaluated the role of PPARγ in PMVEC functions, such as angiogenesis and migration. The role of PPARγ in angiogenesis was evaluated in Tie2CrePPARγ flox/flox and wild-type mice, and in mouse and human PMVECs. RNA sequencing and bioinformatic approaches were utilized to reveal angiogenesisassociated targets for PPARγ. Tie2CrePPARγ flox/flox mice showed an impaired angiogenic capacity. Analysis of endothelial progenitor-like cells using bone marrow transplantation combined with evaluation of isolated PMVECs revealed that loss of PPARγ attenuates the migration and angiogenic capacity of mature PMVECs. PPARγ-deficient human PMVECs showed a similar migration defect in culture. Bioinformatic and experimental analyses newly revealed E2F1 as a target of PPARγ in the regulation of PMVEC migration. Disruption of the PPARγ-E2F1 axis was associated with a dysregulated Wnt pathway related to the GSK3B interacting protein (GSKIP). In conclusion, PPARγ plays an important role in sustaining angiogenic potential in mature PMVECs through E2F1-mediated gene regulation.

show abstract

oPOSSUM: integrated tools for analysis of regulatory motif over-representation

Cited by 153 publications

References 31 publications

Hypoxia-Independent Gene Expression Mediated by SOX9 Promotes Aggressive Pancreatic Tumor Biology

Hypoxia-Independent Gene Expression Mediated by SOX9 Promotes Aggressive Pancreatic Tumor Biology

Actions and interactions of progesterone and estrogen on transcriptome profiles of the bovine endometrium

Loss of PPARγ in endothelial cells leads to impaired angiogenesis

Contact Info

Product

Resources

About