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Identifying genes regulated by Kruppel-like factor-9 by RNA-seq in human glioblastoma stem cells.

ABSTRACT: Kruppel-like factor-9 (KLF9), a member of the large KLF transcription factor family, has emerged as a regulator of oncogenesis, cell differentiation and neural development; however, the molecular basis for KLF9M-bM-^@M-^Ys diverse contextual functions remains unclear. This study focuses on the functions of KLF9 in human glioblastoma stem-like cells. We establish for the first time a genome-wide map of KLF9-regulated targets in human glioblastoma stem-like cells, and show that KLF9 functions as a transcriptional repressor and thereby regulates multiple signaling pathways involved in oncogenesis and stem cell regulation. A detailed analysis of one such pathway, integrin signaling, shows that the capacity of KLF9 to inhibit glioblastoma cell stemness and tumorigenicity requires ITGA6 repression. These findings enhance our understanding of the transcriptional networks underlying cancer cell stemness and differentiation, and identify KLF9-regulated molecular targets applicable to cancer therapeutics. Two cell lines were used as biological replicates. Each cell line has one KLF9 induction sample and one control sample.

ORGANISM(S): Homo sapiens

SUBMITTER: Mingya Ying

PROVIDER: E-GEOD-62212 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Mapping genome-wide binding sites of Kruppel-like factor-9 by ChIP-seq in human glioblastoma stem cells.

Project description:Kruppel-like factor-9 (KLF9), a member of the large KLF transcription factor family, has emerged as a regulator of oncogenesis, cell differentiation and neural development; however, the molecular basis for KLF9M-bM-^@M-^Ys diverse contextual functions remains unclear. This study focuses on the functions of KLF9 in human glioblastoma stem-like cells. We establish for the first time a genome-wide map of KLF9-regulated targets in human glioblastoma stem-like cells, and show that KLF9 functions as a transcriptional repressor and thereby regulates multiple signaling pathways involved in oncogenesis and stem cell regulation. A detailed analysis of one such pathway, integrin signaling, shows that the capacity of KLF9 to inhibit glioblastoma cell stemness and tumorigenicity requires ITGA6 repression. These findings enhance our understanding of the transcriptional networks underlying cancer cell stemness and differentiation, and identify KLF9-regulated molecular targets applicable to cancer therapeutics. Two cell lines were used as biological replicates. Each cell line have one KLF9 ChIP-enriched DNA sample and one input genomic DNA sample.

2014-10-10 | E-GEOD-62211 | biostudies-arrayexpress

Identifying genes regulated by Kruppel-like factor-9 by RNA-seq in human glioblastoma stem cells.

Project description:Kruppel-like factor-9 (KLF9), a member of the large KLF transcription factor family, has emerged as a regulator of oncogenesis, cell differentiation and neural development; however, the molecular basis for KLF9’s diverse contextual functions remains unclear. This study focuses on the functions of KLF9 in human glioblastoma stem-like cells. We establish for the first time a genome-wide map of KLF9-regulated targets in human glioblastoma stem-like cells, and show that KLF9 functions as a transcriptional repressor and thereby regulates multiple signaling pathways involved in oncogenesis and stem cell regulation. A detailed analysis of one such pathway, integrin signaling, shows that the capacity of KLF9 to inhibit glioblastoma cell stemness and tumorigenicity requires ITGA6 repression. These findings enhance our understanding of the transcriptional networks underlying cancer cell stemness and differentiation, and identify KLF9-regulated molecular targets applicable to cancer therapeutics.

2014-10-10 | GSE62212 | GEO

Mapping genome-wide binding sites of Kruppel-like factor-9 by ChIP-seq in human glioblastoma stem cells.

Project description:Kruppel-like factor-9 (KLF9), a member of the large KLF transcription factor family, has emerged as a regulator of oncogenesis, cell differentiation and neural development; however, the molecular basis for KLF9’s diverse contextual functions remains unclear. This study focuses on the functions of KLF9 in human glioblastoma stem-like cells. We establish for the first time a genome-wide map of KLF9-regulated targets in human glioblastoma stem-like cells, and show that KLF9 functions as a transcriptional repressor and thereby regulates multiple signaling pathways involved in oncogenesis and stem cell regulation. A detailed analysis of one such pathway, integrin signaling, shows that the capacity of KLF9 to inhibit glioblastoma cell stemness and tumorigenicity requires ITGA6 repression. These findings enhance our understanding of the transcriptional networks underlying cancer cell stemness and differentiation, and identify KLF9-regulated molecular targets applicable to cancer therapeutics.

2014-10-10 | GSE62211 | GEO

Quantitative phosphoproteome analysis of glioblastoma stem cells

Project description:Glioblastoma is one of the most malignant brain tumors with poor prognosis and their development and progression are known to be driven by glioblastoma stem cells. Although glioblastoma stem cells lose their cancer stemness properties during cultivation in serum-containing medium, little is known about the molecular mechanisms regulating signaling alteration in relation to reduction of stemness. In order to elucidate the global phosphorylation-related signaling events, we performed a SILAC-based quantitative phosphoproteome analysis of serum-induced dynamics in glioblastoma stem cells established from the tumor tissues of the patient. Among a total of 2,876 phosphorylation sites on 1,584 proteins identified in our analysis, 732 phosphorylation sites on 419 proteins were regulated through the alteration of stem cell characteristics.

2016-01-13 | PXD002614 | Pride

Dual role of Integrin alpha-6 in glioblastoma: supporting stemness in proneural stem-like cells while inducing radioresistance in mesenchymal stem-like cells

Project description:Therapeutic resistance after multimodal therapy is the most relevant cause of glioblastoma (GBM) recurrence. Extensive cellular heterogeneity, mainly driven by the presence of GBM stem-like cells (GSC), strongly correlates with patients’ prognosis and limited response to therapies. Defining the mechanisms which drive stemness and control responsiveness to therapy in a GSC-specific manner is therefore mandatory. Here we investigated the role of integrin a6 (ITGA6) in controlling stemness and resistance to radiotherapy in proneural and mesenchymal GSCs subtypes. Using cell sorting, gene silencing, RNA-Seq and in vitro assays, we verified that ITGA6 expression seems crucial for proliferation and stemness of proneural GSCs, while it appears not to be relevant in mesenchymal GSCs under basal conditions. However, when challenged with a fractionated protocol of radiation therapy, comparable to that employed in the clinical setting, mesenchymal GSCs turned out to be dependent on integrin a6 for survival. Specifically, GSCs with reduced levels of ITGA6 displayed a clear reduction of DNA-damage response and perturbation of cell cycle pathways. These data indicate that ITGA6 inhibition is able to overcome the radioresistance of mesenchymal GSCs, while it reduces proliferation and stemness in proneural GSCs. Therefore, integrin a6 controls crucial characteristics across GBM subtypes in GBM heterogeneous biology and thus may represent a promising target to improve patient outcomes

2021-06-30 | GSE178260 | GEO

Extracellular-acidosis restricts one-carbon metabolism and preserves T cell stemness

Project description:The accumulation of acidic metabolic waste products within the tumor microenvironment profoundly inhibits effector functions of tumor-infiltrating lymphocytes (TILs). However, it is unclear whether extracellular-acidosis impacts T cell metabolic fitness and differentiation status. Here, we surprisingly found that prolonged acid exposure reprogrammed T cell intracellular metabolism and mitochondrial fitness, and preserved T cell stemness. Elevated extracellular-acidosis impaired methionine uptake and metabolism via downregulating SLC7A5, therefore altering H3K27me3 deposition at the promoters of crucial T cell stemness genes. These changes promoted the maintenance of a “stem-like memory” state and improved long-term in vivo persistence and anti-tumor efficacy. Our findings not only reveal the unexpected roles of extracellular-acidosis in the maintenance of stem-like properties of T cells, but also advance our understanding of the direct involvement of methionine metabolism in T cell stemness.

2023-01-17 | MTBLS6661 | MetaboLights

The DEAD-box helicase DDX56 is a conserved stemness regulator in normal and cancer stem cells

Project description:A common and shared biology across diverse animal species is that adult tissue homeostasis is ultimately regulated by stem cell proliferation, differentiation, and self-renewal. Aberrant activation of “stemness” programs is deleterious at organismal level, and commonly observed in human cancers. However, identifying key stemness genes in the milieu of thousands of genes dysregulated in a given human cancer is challenging. Here, using a comparative genomics approach between planarians and humans, we identify and functionally screen 76 highly conserved, putative stemness regulators in vivo that are also candidate drivers of stemness in human glioblastoma, a highly aggressive, stem-cell driven cancer with limited treatment options. We selected the helicase DDX56, and demonstrate a conserved role in regulating aspects of stemness across 4 normal and cancer stem cell systems: planarian adult stem cells; mouse embryonic neural stem cells; human glioma neural stem cells; and a fly model of glioblastoma. We demonstrate that DDX56 is required for self-renewal and survival of stem cells across the systems. Using planarians, we show that when DDX56 is lost, stem cells dysregulate expression of ribosomal RNAs and lose nucleolar integrity prior to stem cell death. Altogether, our study demonstrates the power of a comparative genomic approach to discover deeply conserved stemness regulators and actionable target genes relevant to human cancer.

2021-03-01 | GSE159880 | GEO

Klf9 regulates neural stem cell activation and expansion in the adult hippocampus

Project description:Experience governs neurogenesis from radial-glial neural stem cells (RGLs) in the adult hippocampus to support memory. Transcription factors in RGLs integrate physiological signals to dictate quiescence-activation decisions and self-renewal divisions. Whereas asymmetric RGL self-renewal drives neurogenesis during favorable conditions, symmetric divisions prevent premature neurogenesis during unfavorable conditions while amplifying RGLs to anticipate neurogenic demands when conditions become favorable. Here, we show that the transcription factor Kruppel-like factor 9 (Klf9) is enriched in quiescent RGLs and inducible, bidirectional modulation of Klf9 biases RGL quiescence-activation decisions. Clonal lineage tracing and longitudinal intravital two-photon imaging of RGLs following cell-autonomous Klf9 deletion directly demonstrated increased symmetric self-renewal. In vivo translational profiling of RGLs identified a Klf9-dependent blueprint for genetic and metabolic programs instructing RGL quiescence and expansion. Thus, experience dependent regulation of Klf9 in RGLs may ensure self-preservation of neural stem cells while anticipating future demands for neurogenesis and astrogenesis to support hippocampal functions.

2022-01-06 | GSE164889 | GEO

Transcription profiling of jejunums from wild type and Klf9-/- mice to investigate the involvement of Klf9 in small intestine crypt-villus cell renewal and lineage determination.

Project description:Kruppel-like factor 9 (Klf9), a zinc-finger transcription factor, is implicated in the control of cell proliferation, cell differentiation and cell fate in brain and uterus. Using Klf9 null mutant mice, we have investigated the involvement of Klf9 in small intestine crypt-villus cell renewal and lineage determination. We report the predominant expression of Klf9 gene in small intestine smooth muscle (muscularis externa). Jejunums null for Klf9 have shorter villi, reduced crypt stem/transit cell proliferation, and altered lineage determination as indicated by decreased and increased numbers of Goblet and Paneth cells, respectively. A stimulatory role for Klf9 in villus cell migration was demonstrated by BrdU labeling. Results suggest that Klf9 controls the elaboration, from small intestine smooth muscle, of molecular mediator(s) of crypt cell proliferation and lineage determination, and of villus cell migration. Experiment Overall Design: Total RNA was extracted in parallel from the jejunums of five WT and five Klf9-/- male mice (PND 30) using TRIzol reagent (Invitrogen, Carlsbad, CA). Conversion of each RNA preparation to corresponding fragmented cRNA. Fifteen ug of each cRNA was hybridized for 16 hours to an Affymetrix mouse 430A GeneChip. Ten GeneChips (each corresponding to a single animal) were hybridized, washed and scanned in parallel. Following the wash, signal amplification, and signal detection steps, GeneChips were scanned (Agilent GeneArray laser scanner) and the resultant images quantified using Affymetrix MAS 5.0 software.

2007-11-15 | E-GEOD-6443 | biostudies-arrayexpress

Intestinal crypt stem and transit cell proliferation and villus cell migration in mice lacking Klf9

Project description:Krüppel-like factor 9 (Klf9), a zinc-finger transcription factor, is implicated in the control of cell proliferation, cell differentiation and cell fate in brain and uterus. Using Klf9 null mutant mice, we have investigated the involvement of Klf9 in small intestine crypt-villus cell renewal and lineage determination. We report the predominant expression of Klf9 gene in small intestine smooth muscle (muscularis externa). Jejunums null for Klf9 have shorter villi, reduced crypt stem/transit cell proliferation, and altered lineage determination as indicated by decreased and increased numbers of Goblet and Paneth cells, respectively. A stimulatory role for Klf9 in villus cell migration was demonstrated by BrdU labeling. Results suggest that Klf9 controls the elaboration, from small intestine smooth muscle, of molecular mediator(s) of crypt cell proliferation and lineage determination, and of villus cell migration. Keywords: Genetic modification

2006-12-08 | GSE6443 | GEO

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