INSM1 governs a neuronal progenitor state that drives glioblastoma in a human stem cell model
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ABSTRACT:
PROVIDER: PRJNA956944 | ENA |
REPOSITORIES: ENA
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Project description:Glioblastoma (GBM) is an aggressivea lethal brain tumorcancer marked by functional plasticity driven by the interplay between tumor cell-intrinsic mutations and -extrinsic heterogeneity, enabling rapid evolutiontheir interplay with developmental programs. To investigate how canonical GBM glioblastoma mutations promote functional plasticity, we have developeded an isogenic human neural stem cell (NSC) model of glioblastoma GBM by sequential addition of TERT promoter, TP53, and PDGFRA point mutations. TP53 loss-of-function increasesd TERT TERT expression during serial mutagenesis, but only triple mutant NSCs reliably formed lethal brain tumors in vivo that recapitulate glioblastomaGBM. Tumor cell evolution triggersed stress-related metabolic changes and transitionsed toward a neuronal progenitor network driven by transcription factor INSM1. INSM1 is highly expressed in human glioblastoma GBM tumors and, during cortical development, in intermediate progenitor cells (IPC), which give rise to neurons. Remarkably, INSM1 knockdown in triple mutant NSCs and primary glioblastoma GBM cells disrupted disrupts oncogenic gene expression and function and inhibited inhibits the in vivo tumorigenicity of triple mutant NSCs, highlighting the functional importance of an intermediate progenitor cellIPC-like cell state in glioblastoma GBM pathogenesis.
2025-07-15 | GSE229901 | GEO
Project description: Not available
| S-EPMC12764576 | biostudies-literature
Project description:This experiment used RNA-Seq technology to explore gene expression in mouse Insm1^GFP/Pdx1^CFP HIGH [het/het] FACS sorted pancreatic cells (pre-beta cells) and Insm1^GFP/Pdx1^CFP LOW [het/het] cells (other endocrine progenitors) at E15.5 and E18.5. Comparison of Insm1 +/Pdx HIGH and Insm1 +/Pdx LOW cells revealed a set of differentially expressed genes that are required for beta cell specification.
2014-07-01 | E-MTAB-1929 | biostudies-arrayexpress
Project description:Genome-wide Insm1 binding sites analysis revealed an overrepresentation of sequences predicted to bind bHLH and/or forkhead factors, and further analyses demonstrated that most Insm1 sites in the genome are co-occupied by Neurod1 and Foxa2. Binding regions co-occupied by all three factors but not single Insm1 sites explained a significant fraction of gene expression changes in Insm1 mutant β-cells. Together, our data provide evidence that an Insm1, Neurod1 and Foxa2 network maintains a mature gene expression program in β-cells. 6 samples include, replicates of Insm1 and Foxa2, IgG pull down as a control
2015-03-31 | E-GEOD-54046 | biostudies-arrayexpress
Project description:Genome-wide Insm1 binding sites analysis revealed an overrepresentation of sequences predicted to bind bHLH and/or forkhead factors, and further analyses demonstrated that most Insm1 sites in the genome are co-occupied by Neurod1 and Foxa2. Binding regions co-occupied by all three factors but not single Insm1 sites explained a significant fraction of gene expression changes in Insm1 mutant β-cells. Together, our data provide evidence that an Insm1, Neurod1 and Foxa2 network maintains a mature gene expression program in β-cells.
2015-03-31 | GSE54046 | GEO
Project description:Delamination of neural progenitor cells (NPCs) from the ventricular surface is a crucial prerequisite to form the subventricular zone, the germinal layer linked to the expansion of the mammalian neocortex in development and evolution. Here, we dissect the molecular mechanism by which the transcription factor Insm1 promotes the generation of basal progenitors (BPs). Insm1 protein is most highly expressed in newborn BPs in mouse and human developing neocortex. Forced Insm1 expression in embryonic mouse neocortex causes NPC delamination, converting apical to basal radial glia. Insm1 represses the expression of the apical adherens junction belt-specific protein Plekha7. CRISPR/Cas9-mediated disruption of Plekha7 expression suffices to cause NPC delamination. Plekha7 overexpression impedes the intrinsic, and counteracts the Insm1-induced, NPC delamination. Our findings uncover a novel molecular mechanism underlying NPC delamination in which a BP-genic transcription factor specifically targets the integrity of the apical adherens junction belt, rather than adherens junction components as such.
2018-02-15 | GSE109709 | GEO
Project description:The zinc finger factor Insm1 is known to regulate differentiation of pancreatic ? cells during development, Here we show that Insm1 is essential for the maintenance of functionally mature pancreatic ? cells in mice. We used microarrays to analyse the global gene expression after deletion of insm1 in adult pancreatic ? cells and identified functional important genes and immature islets releated genes deregulated in the mutatant islets. We used 8 mutant and 8 litter matched control mice for the islets preparation.
2015-03-31 | E-GEOD-54044 | biostudies-arrayexpress
Project description:Neuroblastoma (NB), a pediatric cancer of sympatho-adrenal (SA) lineage, is marked by disrupted differentiation and cellular heterogeneity. INSM1, a zinc-finger transcription factor, is highly expressed in NB and developing SA tissues, where it regulates neuroendocrine differentiation, especially in chromaffin cells. We investigated INSM1’s role in maintaining an undifferentiated, progenitor-like state in NB and its regulation via metabolic and epigenetic mechanisms. Transcriptomic profiling, promoter assays, and metabolic flux analysis revealed that INSM1 expression correlates with methionine cycle activity, particularly the S-adenosylmethionine (SAM)/S-adenosylhomocysteine (SAH) ratio. Disruption of SAM/SAH balance altered INSM1 promoter activity and histone methylation, implicating epigenetic control in NB cell fate. Retinoic acid-induced differentiation downregulated INSM1 and N-Myc, linking INSM1 to tumor cell immaturity. INSM1 overexpression in SH-SY-5Y cells upregulated neuroendocrine and thyroid hormone-related genes (CHGA, CHGB, DDC, NCAM1, DIO3, TH), while suppressing genes involved in cell cycle (MYBL2, RRM, CDC25A), methionine metabolism (AHCY, MAT2A), transcriptional regulation (EZH2), and oncogenic signaling (ALK, LINC011667). These findings suggest that INSM1 promotes NB aggressiveness by sustaining a neuroendocrine progenitor-like phenotype through metabolic-epigenetic coupling.
2025-12-17 | GSE312485 | GEO
Project description:Insm1, encoding a zinc finger protein, is expressed specifically in neuroendocrine cells. Recent study showed the first evidence of Insm1 expression in medullary thymic epithelial cells (mTEC). Here we investigated the expression and function of Insm1 in mTEC. Mutation of Insm1 resulted in decreased proportion of mTEChi although normal development of other types of thymic cells. We detected altered expression of a subset of tissue-restricted antigens (TRAs) and mild decreased expression of Aire and Fezf2 in Insm1 mutant mTEC. We further showed that Insm1 recognizes a DNA sequence which is similar to the CCCTC-Binding factor (CTCF) binding motif. Mutation of Insm1 altered CTCF binding genome widely and thus the expression of genes. In nude mice transplanted with Insm1 mutant thymus, autoimmune responses were observed in multiple peripheral tissues. In thymus specific Insm1 mutant mice, we detected decreased induction of regulatory T (Treg) cells in the thymus, obvious lymphocytes infiltration and autoimmune antibody reaction in several peripheral tissues. In thymic epithelial cells specific Insm1 overexpression mice, we detected enlarged mTEC proportion and increased expression of mTEC specific genes. Thus, we suggest that Insm1 is a novel regulator of mTEC function and autoimmunity.
2024-01-01 | GSE193927 | GEO
Project description:Insm1, encoding a zinc finger protein, is expressed specifically in neuroendocrine cells. Recent study showed the first evidence of Insm1 expression in medullary thymic epithelial cells (mTEC). Here we investigated the expression and function of Insm1 in mTEC. Mutation of Insm1 resulted in decreased proportion of mTEChi although normal development of other types of thymic cells. We detected altered expression of a subset of tissue-restricted antigens (TRAs) and mild decreased expression of Aire and Fezf2 in Insm1 mutant mTEC. We further showed that Insm1 recognizes a DNA sequence which is similar to the CCCTC-Binding factor (CTCF) binding motif. Mutation of Insm1 altered CTCF binding genome widely and thus the expression of genes. In nude mice transplanted with Insm1 mutant thymus, autoimmune responses were observed in multiple peripheral tissues. In thymus specific Insm1 mutant mice, we detected decreased induction of regulatory T (Treg) cells in the thymus, obvious lymphocytes infiltration and autoimmune antibody reaction in several peripheral tissues. In thymic epithelial cells specific Insm1 overexpression mice, we detected enlarged mTEC proportion and increased expression of mTEC specific genes. Thus, we suggest that Insm1 is a novel regulator of mTEC function and autoimmunity.
2024-01-01 | GSE193926 | GEO