Transcription factors ASCL1 and OLIG2 drive glioblastoma initiation and co-regulate tumor cell types and migration [ChIP-seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE247977 | GEO | 2024/06/30
REPOSITORIES: GEO
Similar Datasets
Project description:Glioblastomas (GBMs) are highly aggressive, infiltrative, and heterogeneous brain tumors driven by complex genetic alterations. The basic-helix-loop-helix (bHLH) transcription factors ASCL1 and OLIG2 are dynamically co-expressed in GBMs; however, their combinatorial roles in regulating the plasticity and heterogeneity of GBM cells are unclear. Here, we show that induction of somatic mutations in subventricular zone (SVZ) progenitor cells leads to the dysregulation of ASCL1 and OLIG2, which then function redundantly and are required for brain tumor formation in a mouse model of GBM. Subsequently, the binding of ASCL1 and OLIG2 to each other’s loci and to downstream target genes then determines the cell types and degree of migration of tumor cells. Single-cell RNA sequencing (scRNA-seq) reveals that a high level of ASCL1 is key in specifying highly migratory neural stem cell (NSC)/astrocyte-like tumor cell types, which are marked by upregulation of ribosomal protein, oxidative phosphorylation, cancer metastasis, and therapeutic resistance genes.
2024-06-30 | GSE247650 | GEO
Project description:The basic helix-loop-helix proteins Olig1 and Olig2 are expressed in high grade, aggressive human glioblastoma multiformes (GBMs). Here we investigated genetic mechanisms regulating Olig1/2 function during gliomagenesis. Although Olig2 function is necessary for early-aggressive tumor formation in a genetically relevant model of classic GBMs with intact p53 function, late-onset gliomas do eventually form. Using an unbiased approach, we identified Id4, encoding a negative HLH protein, as a gene target potently repressed by Olig2 in glioma progenitors. Although Id4 is thought to antagonize proneural genes involved in differentiation, we report a paradoxical role for Id4 in glioma. Genetic deletion of Id4 converts Olig2-/- gliomas to the early-aggressive form, and conversely, overexpression of Id4 inhibits intact Olig2 and prevents even late-onset tumors. Olig1 overexpression is sufficient for gliomagenesis in an Id4-dependent manner. Together, these findings indicate that gliomagenic factors Olig1 and Olig2 are opposed by Id4 function, which acts as tumor suppressor in p53-intact gliomas.
2018-01-02 | GSE44151 | GEO
Project description:Distinct neural stem cells reside in different regions of the subventricular zone and generate multiple olfactory bulb interneuron subtypes in the adult mouse brain. This study shows that the basic helix-loop-helix type transcription factor Olig2 defines a ventrally enriched subset of NSCs in the early postnatal and adult SVZ and plays an important role in the subtype specification of olfactory bulb interneurons produced by adult NSCs.
2022-02-18 | GSE174392 | GEO
Project description:In this study, we explored the transcriptomic consequences of strong activation of the Notch pathway in embryonic human neural stem cells and in gliomas. For this we used a forced expression of the Notch intracellular domain (NICD). Glioblastoma multiforms (GBMs) are highly vascularized brain tumors containing a subpopulation of multipotent cancer stem cells. These cells closely interact with endothelial cells in neurovascular niches. In this study we have uncovered a close link between the Notch1 pathway and the tumoral vascularization process of GBM stem cells. We observed that although the Notch1 receptor was activated, the typical target proteins (HES5, HEY1, HEY2) were not or barely expressed in two explored GBM stem cell cultures. Notch1 signalling activation by expression of the intracellular form (NICD) in these cells was found to reduce their growth rate and migration which was accompanied by the sharp reduction of neural stem cell transcription factor expression (ASCL1, OLIG2, SOX2) while HEY1/2, KLF9, SNAI2 transcription factors were upregulated. Expression of OLIG2 and growth were restored after termination of Notch1 stimulation. Remarkably, NICD expression induced the expression of pericyte cell markers (NG2, PDGFRb and a-smooth muscle actin (aSMA)) in GBM stem cells. This was paralleled with the induction of several angiogenesis-related factors most notably cytokines (HB-EGF, IL8, PLGF), metalloprotease (MMP9) and adhesion proteins (VCAM-1, ICAM-1, ITGA9). In xenotransplantation experiments, contrasting with the infiltrative and poorly-vascularized tumors obtained with control GBM stem cells, Notch1 stimulation resulted in poorly-disseminating but highly-vascularized grafts containing large vessels with lumen. Notch1-stimulated GBM cells expressed pericyte cell markers and closely associated with endothelial cells. These results reveal an important role for the Notch1 pathway in regulating GBM stem cell plasticity and angiogenic properties. Embryonic human neural progenitors obtained from Lonza, the U87 glioma cell line, and glioma cancer stem cells (Gb4 and Gb7) characterized in Guichet et al. (Glia, 2013, 61(2), 225-39) were infected with lentiviruses expressing YFP or YFP-IRES-NICD (activated form of Notch receptor). After 48h, RNA were extracted for Affymetrix microarray analysis.
2014-06-04 | E-GEOD-44561 | biostudies-arrayexpress
Project description:Several basic helix-loop-helix (bHLH) transcription factors are upregulated in Sonic Hedgehog subgroup of medulloblastoma (SHH MB). Olig2, a neural bHLH transcription factor known to regulate differentiation of neural cell populations, is broadly expressed in mouse models of SHH MB. ChIP-Seq of Olig2 revealed its binding to a large number of sites near genes known to promote SHH MB tumorigenesis, suggesting a potential role for Olig2 in regulating transcriptional programme of MB.
2024-03-23 | GSE103824 | GEO
Project description:Previous lineage analyses have shown that retinal progenitor cells (RPCs) are multipotent throughout development, and expression profiling studies have shown a great deal of molecular heterogeneity among RPCs. To determine if the molecular heterogeneity predicts that an RPC will produce particular types of progeny, clonal lineage analysis was used to investigate the progeny of a subset of RPCs, those that express the basic helix-loop-helix (bHLH) transcription factor, Olig2. In contrast to the large and complex set of clones generated by viral marking of random embryonic RPCs, the embryonic Olig2+ RPCs underwent terminal divisions, producing small clones with primarily two of the five cell types being made by the pool of RPCs at that time. The embryonically produced cell types made by Olig2+ RPCs were cone photoreceptors and horizontal cell (HC) interneurons. Moreover, the embryonic Olig2+ RPC did not make the later Olig2+ RPC. The later, postnatal Olig2+ RPCs also made terminal divisions, which were biased towards production of rod photoreceptors and amacrine cell (AC) interneurons. These data indicate that the multipotent progenitor pool is made up of distinctive types of RPCs, which have biases towards producing subsets of retinal neurons in a terminal division, with the types of neurons produced varying over time. This strategy is similar to that of the developing Drosophila melanogaster ventral nerve cord, with the Olig2+ cells behaving as ganglion mother cells. Single retinal cells were isolated in tubes containing lysis buffer, their mRNAs were reverse transcribed, and the resulting cDNAs were PCR amplified for 35 cycles. Labeled cDNA samples were hybridized to Affymetrix 430 2.0 microarrays and the data was normalized using MAS5.0 software. These cells were examined for the expression of Olig2 or other bHLH factors.
2012-04-12 | E-GEOD-37207 | biostudies-arrayexpress
Project description:Previous lineage analyses have shown that retinal progenitor cells (RPCs) are multipotent throughout development, and expression profiling studies have shown a great deal of molecular heterogeneity among RPCs. To determine if the molecular heterogeneity predicts that an RPC will produce particular types of progeny, clonal lineage analysis was used to investigate the progeny of a subset of RPCs, those that express the basic helix-loop-helix (bHLH) transcription factor, Olig2. In contrast to the large and complex set of clones generated by viral marking of random embryonic RPCs, the embryonic Olig2+ RPCs underwent terminal divisions, producing small clones with primarily two of the five cell types being made by the pool of RPCs at that time. The embryonically produced cell types made by Olig2+ RPCs were cone photoreceptors and horizontal cell (HC) interneurons. Moreover, the embryonic Olig2+ RPC did not make the later Olig2+ RPC. The later, postnatal Olig2+ RPCs also made terminal divisions, which were biased towards production of rod photoreceptors and amacrine cell (AC) interneurons. These data indicate that the multipotent progenitor pool is made up of distinctive types of RPCs, which have biases towards producing subsets of retinal neurons in a terminal division, with the types of neurons produced varying over time. This strategy is similar to that of the developing Drosophila melanogaster ventral nerve cord, with the Olig2+ cells behaving as ganglion mother cells.
2012-04-13 | GSE37207 | GEO
Project description:Glioblastoma multiforme (GBM), a grade IV astrocytoma, is the most common and aggressive brain tumor in adults, characterized by being highly infiltrative, angiogenic, and resistant to chemotherapy and radiotherapy. In previous works, has been determined that progesterone P4 increases proliferation, migration and invasion of cells derived from human GBMs through the interaction with its intracellular receptor (PR). In breast cancer, there exist evidence that P4 regulates the expression of miRNAs with tumor suppressor or oncogenic action, via the classical PR. The signature of miRNAs affected by P4 treatment in cells derived from human GBMs has not been determined. Therefore, we studied the effect of P4 on miRNAs expression pattern in U251 cells derived from a human GBM.
2020-01-25 | GSE144204 | GEO
Project description:In this study, we explored the transcriptomic consequences of strong activation of the Notch pathway in embryonic human neural stem cells and in gliomas. For this we used a forced expression of the Notch intracellular domain (NICD). Glioblastoma multiforms (GBMs) are highly vascularized brain tumors containing a subpopulation of multipotent cancer stem cells. These cells closely interact with endothelial cells in neurovascular niches. In this study we have uncovered a close link between the Notch1 pathway and the tumoral vascularization process of GBM stem cells. We observed that although the Notch1 receptor was activated, the typical target proteins (HES5, HEY1, HEY2) were not or barely expressed in two explored GBM stem cell cultures. Notch1 signalling activation by expression of the intracellular form (NICD) in these cells was found to reduce their growth rate and migration which was accompanied by the sharp reduction of neural stem cell transcription factor expression (ASCL1, OLIG2, SOX2) while HEY1/2, KLF9, SNAI2 transcription factors were upregulated. Expression of OLIG2 and growth were restored after termination of Notch1 stimulation. Remarkably, NICD expression induced the expression of pericyte cell markers (NG2, PDGFRb and a-smooth muscle actin (aSMA)) in GBM stem cells. This was paralleled with the induction of several angiogenesis-related factors most notably cytokines (HB-EGF, IL8, PLGF), metalloprotease (MMP9) and adhesion proteins (VCAM-1, ICAM-1, ITGA9). In xenotransplantation experiments, contrasting with the infiltrative and poorly-vascularized tumors obtained with control GBM stem cells, Notch1 stimulation resulted in poorly-disseminating but highly-vascularized grafts containing large vessels with lumen. Notch1-stimulated GBM cells expressed pericyte cell markers and closely associated with endothelial cells. These results reveal an important role for the Notch1 pathway in regulating GBM stem cell plasticity and angiogenic properties.
2014-06-04 | GSE44561 | GEO
Project description:Myelination by oligodendrocytes in the central nervous system (CNS) is essential for proper brain function, yet the molecular determinants that control this process remain poorly understood. The basic helix-loop-helix transcription factors Olig1 and Olig2 promote myelination, whereas bone morphogenetic protein (BMP) and Wnt/?-catenin signaling inhibit myelination. Here we show that these opposing regulators of myelination are functionally linked by the Olig1/2 common target Smad-interacting protein-1 (Sip1). We demonstrate that Sip1 is an essential modulator of CNS myelination. Sip1 represses differentiation inhibitory signals by antagonizing BMP receptor-activated Smad activity while activating crucial oligodendrocyte-promoting factors. Importantly, a key Sip1-activated target, Smad7, is required for oligodendrocyte differentiation and partially rescues differentiation defects caused by Sip1 loss. Smad7 promotes myelination by blocking the BMP- and ?-catenin-negative regulatory pathways. Thus, our findings reveal that Sip1-mediated antagonism of inhibitory signaling is critical for promoting CNS myelination and point to new mediators for myelin repair. ChIP-seq was performed to identify Olig2 direct target genes in oligodendrocytes during oligodendrocyte differentiation.
2012-08-31 | E-GEOD-40506 | biostudies-arrayexpress