Clinical Significance: Understanding the differences in colorectal cancer (CRC) aggressiveness and clinical outcomes in relation to tumor stage and different molecular subsets is at most important for designing treatment regimens. However, molecular signatures for specific phenotypic subsets that predict the aggressiveness and clinical outcomes of CRC, specifically in advanced disease stage are lacking. Therefore, for the first time, the current study has identified a set of molecular markers that are associated with aggressive Stage III CRCs that exhibited microsatellite stable and mutant p53 phenotypic features. These findings might aid in designing aggressive treatment regimens and help to provide insights into the development of novel therapeutic targets.
Prognostic significance and gene expression profiles of p53 mutations in microsatellite-stable stage III colorectal adenocarcinomas.
Specimen part, Disease, Disease stage
View SamplesOligodendrocytes (OLs) and myelin are critical for normal brain function and they have been implicated in neurodegeneration. Human neuroimaging studies have demonstrated that alterations in axons and myelin occur early in Alzheimer's Disease (AD) course. However, the molecular mechanism underlying the role of OLs in AD remains largely unknown. In this study, we systematically interrogated OL-enriched gene networks constructed from large-scale genomic, transcriptomic, and proteomic data in human AD postmortem brain samples. These robust OL networks were highly enriched for genes associated with AD risk variants, including BIN1. We corroborated the structure of the AD OL coexpression and gene-gene interaction networks through ablation of genes identified as key drivers of the networks, including UGT8, CNP, MYRF, PLP1, NPC1, and NDGR1. Perturbations of these key drivers not only caused dysregulation in their associated network neighborhoods, but also mimicked pathways of gene expression dysregulation seen in human AD postmortem brain samples. In particular, the OL subnetwork controlled by the AD risk gene PSEN1 was strongly dysregulated in AD, suggesting a potential role of PSEN1 in disrupting the myelination pathway towards the onset of AD. In summary, this study built and systematically validated the first comprehensive molecular blueprint of OL dysregulation in AD, and identified key OL- and myelination-related genes and networks as potential candidate targets for the future development of AD therapies. Overall design: The mouse knockout models have been previously described for each of Ugt8 (Coetzee et al., 1996), Cnp (Lappe-Siefke et al., 2003), and Plp1 (Klugmann et al., 1997). For each of the two conditions studied (control and homozygous knockout mice), five mice of either sex were sacrificed at postnatal day 20 and brains were flashed-frozen until analysis. The frontal cortex (FC) and cerebellum (CBM) were dissected out and individually processed. RNA was isolated using Trizol reagent and processed using Ribo-Zero rRNA removal. RNA-sequencing was performed using the Illumina HiSeq2000 with 100 nucleotide paired-end reads. RNA-sequencing reads were mapped to the mouse genome (mm10, UCSC assembly) using Bowtie (version 2.2.3.0), TopHat (version 2.0.11), and SamTools (version 0.1.19.0) using a read length of 100. Reads were converted to counts at the gene level using HTSeq on the BAM files from TopHat2 using the UCSC known genes data set.
Multiscale network modeling of oligodendrocytes reveals molecular components of myelin dysregulation in Alzheimer's disease.
Specimen part, Subject
View SamplesRearrangements involving the NUP98 gene resulting in fusions to several partner genes occur in acute myeloid leukemia and myelodysplastic syndromes. This study demonstrates that the second FG repeat domain of the NUP98 moiety of the NUP98-HOXA9 fusion protein is important for its cell immortalization and leukemogenesis activities. We demonstrate that NUP98-HOXA9 interacts with MLL via this FG repeat domain and that, in the absence of MLL, NUP98-HOXA9-induced cell immortalization and leukemogenesis are severely inhibited. Molecular analyses indicate that MLL is important for the recruitment of NUP98-HOXA9 to the HOXA locus and for NUP98-HOXA9-induced HOXA gene expression. Our data indicate that MLL is crucial for NUP98-HOXA9 leukemia initiation.
MLL is essential for NUP98-HOXA9-induced leukemia.
No sample metadata fields
View SamplesRegeneration of fragmented Drosophila imaginal discs occurs in an epimorphic manner, involving local cell proliferation at the wound site. Following disc fragmentation, cells at the wound site activate a restoration program through wound healing, regenerative cell proliferation and repatterning of the tissue. However, the interplay of signaling cascades, driving these early reprogramming steps, is not well understood. Here we profiled the transcriptome of regenerating cells in the early phase within twenty-four hours after wounding. We found that JAK/STAT signaling becomes activated at the wound site and promotes regenerative cell proliferation in cooperation with Wingless (Wg) signaling. In addition, we demonstrated that the expression of Drosophila insulin-like peptide 8 (dilp8), which encodes a paracrine peptide to delay the onset of pupariation, is controlled by JAK/STAT signaling in early regenerating discs. Our findings suggest that JAK/STAT signaling plays a pivotal role in coordinating regenerative disc growth with organismal developmental timing.
During Drosophila disc regeneration, JAK/STAT coordinates cell proliferation with Dilp8-mediated developmental delay.
Sex, Specimen part, Treatment
View SamplesGlioblastomas show heterogeneous histological features. These distinct phenotypic states are thought to be associated with the presence of glioma stem cells (GSCs), which are highly tumorigenic and self-renewing sub-population of tumor cells that have different functional characteristics. To investigate gene expression including lncRNA (long non-coding RNA) in GSC, we have performed high-throughput RNA-sequencing (RNA-seq) experiment using Illumina GAIIx. Overall design: Profiles of gene expression including lncRNA in GSC were generated by RNA-seq using Illumina GAIIx.
Targeting the Notch-regulated non-coding RNA TUG1 for glioma treatment.
No sample metadata fields
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Integrative genomics of gene and metabolic regulation by estrogen receptors α and β, and their coregulators.
Specimen part, Cell line
View SamplesThe closely related transcription factors (TFs), estrogen receptors ER and ER, regulate divergent gene expression programs and proliferative outcomes in breast cancer. Utilizing MCF-7 breast cancer cells with ER, ER, or both receptors as a model system to define the basis of differing response specification by related TFs, we show that these TFs and their key coregulators, SRC3 and RIP140, generate overlapping as well as unique chromatin-binding and transcription-regulating modules.
Integrative genomics of gene and metabolic regulation by estrogen receptors α and β, and their coregulators.
Specimen part, Cell line
View SamplesWe used microarrays to detail the global transcriptional response mediated by ERalpha or ERbeta to the phytoestrogen genistein in the MCF-7 human breast cancer cell model.
Estrogen Receptors alpha and beta as determinants of gene expression: influence of ligand, dose, and chromatin binding.
No sample metadata fields
View SamplesThe MCF-7 were infected with either control adenovirus expressing B-galactosidase (Ad) or adenovirus expressing ERB (AdERbeta) for 72 h. For knockdown of the endogenous ERa in MCF-7 cells, cells were treated with siRNA for 24h (AdERbeta+SiERalpha). Then cells were treated with Veh (0.1% EtOH), 10 nM E2 or 1 uM BEs (botanical extracts) for 24h. Overall design: Duplicate samples run; treatment after knockdown included a control treatment (V), estradiol (E2) or botanical extracts; genistein (Gen), S-equol, liquiritigenin (Liq)
Transcriptomic analysis identifies gene networks regulated by estrogen receptor α (ERα) and ERβ that control distinct effects of different botanical estrogens.
No sample metadata fields
View SamplesDrosophila imaginal disc cells exhibit a remarkable ability to switch cell fates under various perturbations, a phenomenon known as transdetermination (TD). The winged eye (wge) gene induces eye-to-wing TD by its overexpression in eye imaginal discs using eye specific Gal4 driver (eyeless-Gal4). Gene network controlling this process, however, is largely unclear. Additionally, we identified that heterochromatin-related histone methyltransferase Su(var)3-9 is essential for wge-mediated TD.
winged eye Induces Transdetermination of Drosophila Imaginal Disc by Acting in Concert with a Histone Methyltransferase, Su(var)3-9.
Specimen part
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