Pancreatic Ductal Adenocarcinoma (PDA) develops predominantly through pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasm (IPMN) precursor lesions. Pancreatic acinar cells are reprogrammed to a “ductal like” state during PanIN-PDA formation. Here, we demonstrate a parallel mechanism operative in mature duct cells where they undergo “ductal retrogression” to form IPMN-PDA. Brg1, a catalytic subunit of the SWI/SNF complexes, plays a critical antagonistic role in IPMN-PDA development. In mature duct cells Brg1 inhibits the dedifferentiation that precedes neoplastic transformation, thus attenuating tumor initiation. In contrast, Brg1 promotes tumorigenesis in full-blown PDA by supporting a mesenchymal-like transcriptional landscape. We have exploited this duality of Brg1 functions to develop a novel therapeutic approach using an epigenetic drug JQ1. In summary, this study demonstrates the context-dependent roles of Brg1 and points to potential therapeutic treatment options based on epigenetic regulation in PDA. Overall design: Duct cells were isolated from mice of 3 different genotypes and duct cells from 3 mice of each genotype were sequenced. For the put back experiments, control retrovirus and that expressing Brg1 were transdcued in Brg1 null IPMN mouse cell line.
Brg1 promotes both tumor-suppressive and oncogenic activities at distinct stages of pancreatic cancer formation.
No sample metadata fields
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Endothelial GATA4 controls liver fibrosis and regeneration by preventing a pathogenic switch in angiocrine signaling.
Specimen part, Treatment
View SamplesLiver sinusoidal endothelial cells (LSEC) constitute discontinuous, permeable microvessels, with a characteristic program of gene expression that differs significantly from continuous microvascular endothelial cells e.g. in the lung. Gata4 is described as master regulator of LSEC specification during liver development. Here, we sought to analyze the role of endothelial Gata4 in the adult liver.
Endothelial GATA4 controls liver fibrosis and regeneration by preventing a pathogenic switch in angiocrine signaling.
Specimen part
View SamplesLiver sinusoidal endothelial cells (LSEC) constitute discontinuous, permeable microvessels, with a characteristic program of gene expression that differs significantly from continuous microvascular endothelial cells e.g. in the lung. LSEC play a pivotal role in liver fibrogenesis in the CDAA dietary model of non-alcoholic steatohepatitis (NASH).
Endothelial GATA4 controls liver fibrosis and regeneration by preventing a pathogenic switch in angiocrine signaling.
Specimen part, Treatment
View SamplesLiver sinusoidal endothelial cells (LSEC) constitute discontinuous, permeable microvessels, with a characteristic program of gene expression that differs significantly from continuous microvascular endothelial cells e.g. in the lung. Gata4 is described as master regulator of LSEC specification during liver development. Here, we sought to analyze the role of endothelial Gata4 in the adult liver.
Endothelial GATA4 controls liver fibrosis and regeneration by preventing a pathogenic switch in angiocrine signaling.
Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
DNMT1-interacting RNAs block gene-specific DNA methylation.
Cell line, Treatment
View SamplesWe used the microarray analysis to detail the gene expression profile from the leukemic cell line HL-60
DNMT1-interacting RNAs block gene-specific DNA methylation.
Cell line
View SamplesIdentification of the all RNA species associated with DNMT1. Using a comparative genome-scale approach we identified and correlated the RNA species physically associated with DNMT1 and proximal to the annotated genes to the methylation status of the corresponding loci and expression levels of the respective genes. This comparative approach delineated the first -DNMT1 centered- 'epitranscriptome' map, a comprehensive map cross-referencing DNMT1-interacting transcripts to (i) DNA methylation and (ii) gene expression profile. Overall design: Relationship between DNMT1-RNA interactions, DNA methylation and gene expression
DNMT1-interacting RNAs block gene-specific DNA methylation.
Cell line, Subject
View SamplesAneuploidy, i.e., variation in the number of individual chromosomes (chromosomal aneuploidy) or chromosome segment (segmental aneuploidy) is associated with developmental abnormalities and reduced fitness in all species examined, is the leading cause of miscarriages and mental retardations and a hallmark of cancer. Despite their documented importance in disease the effects of aneuploidies on the transcriptome remains largely unknown. Here we have examined the expression output in seven deficiency heterozygotes as single deficiencies and in all pairwise combinations. The results show that genes in one copy are buffered, i.e., are expressed above the expected 50% expression level compared to wild type and the buffering is general and not influenced by additional haploid regions. Long genes are significantly better buffered than short genes and our analysis suggests that gene length is the primary determinant for the degree of buffering. For short genes the degree of buffering depends on expression level and expression pattern. Furthermore, the results show that in deficiency heterozygotes the expression of genes involved in proteolysis is enhanced and negatively correlates with the degree of buffering. Our results suggest that proteolysis is a general response induced by aneuploidy.
Buffering and proteolysis are induced by segmental monosomy in Drosophila melanogaster.
Sex
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Integrative analysis of SF-1 transcription factor dosage impact on genome-wide binding and gene expression regulation.
Specimen part, Cell line, Treatment
View Samples