Snail is a zinc-finger transcription factor best known for its ability to down-regulate E-cadherin. Its established significance in embryology and organogenesis has been expanded to include a role in the tumor progression of a number of human cancers. In addition to E-cadherin, it has more recently been associated with the down-regulation and up-regulation of a number of other genes that affect important malignant phenotypes.
Snail promotes CXCR2 ligand-dependent tumor progression in non-small cell lung carcinoma.
Cell line
View SamplesCancer progression is associated with alterations of epigenetic regulators such as histone-lysine demethylases 4 (KDM4)2-5. During breast cancer therapy, classical treatments fail to address resistant cancer stem cell populations6-10. Here, we identified a novel KDM4 inhibitor (KDM4(i)) with unique preclinical characteristics. KDM4(i) is a highly potent pan KDM4 inhibitor that specifically blocks the demethylase activity of KDM4A, B, C, and D but not that of the other members of the KDM family. We validated the KDM4(i) anti-tumoral properties under conditions recapitulating patient tumors. Therefore, we established a method to isolate and grow triple-negative breast cancer stem cells (BCSCs) from individual patient tumors after neoadjuvant chemotherapy. Limiting dilution orthotopic xenografts of these BCSCs faithfully regenerate original patient tumor histology and gene expression. KDM4(i) blocks proliferation, sphere formation and xenograft tumor growth of BCSCs. Importantly, KDM4(i) abrogates expression of EGFR, a driver of therapy-resistant triple-negative breast tumor cells11, via inhibition of the KDM4A demethylase activity. Taken together, we present a unique BCSC culture system as a basis for therapeutic compound identification and demonstrate that KDM4 inhibition is a new therapeutic strategy for the treatment of triple-negative breast cancer.
KDM4 Inhibition Targets Breast Cancer Stem-like Cells.
Sex, Specimen part, Subject
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Enhancing dopaminergic signaling and histone acetylation promotes long-term rescue of deficient fear extinction.
Sex, Specimen part
View SamplesBackground: Extinction-based exposure therapy is used in treating anxiety- and trauma-related disorders, however there is the need to improve its limited efficacy in individuals with impaired fear extinction learning and to facilitate the inadequate protection against return-of-fear phenomena.
Enhancing dopaminergic signaling and histone acetylation promotes long-term rescue of deficient fear extinction.
Sex, Specimen part
View SamplesBackground: Extinction-based exposure therapy is used in treating anxiety- and trauma-related disorders, however there is the need to improve its limited efficacy in individuals with impaired fear extinction learning and to facilitate the inadequate protection against return-of-fear phenomena.
Enhancing dopaminergic signaling and histone acetylation promotes long-term rescue of deficient fear extinction.
Sex, Specimen part
View SamplesArgonaute (Ago) proteins associate with microRNAs (miRNAs), which guide them to complementary target mRNAs resulting in gene silencing.
Phosphorylation of Argonaute proteins affects mRNA binding and is essential for microRNA-guided gene silencing <i>in vivo</i>.
Cell line
View SamplesC/EBPalpha is a transcription factor critically involved in myeloid development and indispensable for formation of granulocytes. To track the cellular fate of stem and progenitor (LSK) cells, which express C/EBPalpha, we developed a mouse model expressing Cre recombinase from the Cebpa promoter and an inducible EYFP allele. We show that Cebpa/EYFP+ cells represent a significant subset of LSK cells, which predominantly give rise to myeloid cells in steady state hematopoiesis.
Lineage-instructive function of C/EBPα in multipotent hematopoietic cells and early thymic progenitors.
Specimen part
View SamplesRNA-seq data of crwn1, crwn2, crwn4, crwn1 crwn2 and crwn1 crwn4
Loss of CRWN Nuclear Proteins Induces Cell Death and Salicylic Acid Defense Signaling.
Age, Specimen part
View SamplesIt is currently accepted that the human brain has a limited neurogenic capacity and an impaired regenerative potential. We have previously shown the existence of CD271-expressing neural stem cells (NSCs) in the subventricular zone (SVZ) of Parkinson's disease (PD) patients, which proliferate and differentiate towards neurons and glial cells in vitro. To study the molecular profile of these NSCs in detail, we performed RNA sequencing and mass spectrometry on CD271+ NSCs isolated from human post-mortem SVZ and on homogenates of the SVZ. CD271+ cells were isolated through magnetic cell separation (MACS). We first compared the molecular profile of CD271+ NSCs to the SVZ homogenate from control donors to assess the CD271+ NSCs gene signature and finally made a comparison between controls and PD patients to establish a specific molecular profile of NSCs and the SVZ in PD. While our transcriptome analysis did not identify any differentially expressed genes in the SVZ between control and PD patients, our proteome analysis revealed several proteins that were differentially expressed in PD. Some of these proteins are involved in cytoskeletal organization and mitochondrial function. Transcriptome and proteome analyses of NSCs from PD revealed changes in the expression of genes and proteins involved in metabolism, transcriptional activity and cytoskeletal organization. Our results not only confirm pathological hallmarks of PD (e.g. impaired mitochondrial function), but also suggest that NSCs may transit into a primed-quiescent state, that is in an “alert” non-proliferative phase in PD. Overall design: From post-mortem human SVZ of control and Parkinson disease donors we isolated CD271+ NSCs and Cd11b+ microglia by MACS and the whole SVZ to generate RNA sequencing libraries using Celseq2 method. We aimed for low coverage sequencing (~2 million mapped to the coding regions) per sample to investigate the gross changes in the transcriptome. Libraries (rpi small primer) were sequenced in 3 runs, 2 on an Illumina NextSeq500 using 75-bp paired-end sequencing at the Utrecht Seuqencing center (USEQ) and the third on a HiSeq4000 using 150-bp paired-end sequencing at Genomescan. All the samples were mapped in a single run to an average depth of ~10 million reads per sample. Reads were mapped to the latest human coding transcriptome using bwa, normalized and analyzed using the standard DESEQ2 package.
Transcriptome and proteome profiling of neural stem cells from the human subventricular zone in Parkinson's disease.
Specimen part, Subject
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Regulation of transcriptional elongation in pluripotency and cell differentiation by the PHD-finger protein Phf5a.
Specimen part, Cell line
View Samples