Analysis of chromatin accessibility uncovers TEAD1 as a regulator of migration in human glioblastoma
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA482999 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7607810_1.fastq.gz | Fastqsanger.gz | |||
| SRR7607810_2.fastq.gz | Fastqsanger.gz | |||
| SRR7607820_1.fastq.gz | Fastqsanger.gz | |||
| SRR7607820_2.fastq.gz | Fastqsanger.gz | |||
| SRR7607830_1.fastq.gz | Fastqsanger.gz |
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Project description:The intrinsic drivers of migration in glioblastoma (GBM) are poorly understood. To better capture the native molecular imprint of GBM and its developmental context, we isolate human stem cell populations from GBM (GSC) and germinal matrix tissues and map their chromatin accessibility via ATAC-seq. We uncover two distinct regulatory GSC signatures, a developmentally-shared/proliferative and a tumor-specific/migratory one in which TEAD1/4 motifs are uniquely overrepresented. Using ChIP-PCR we validate TEAD1 trans occupancy at accessibility sites within EGFR, AQP4, and CDH4. To further characterize TEAD’s functional role in GBM, we knockout TEAD1 or TEAD4 in patient-derived GBM lines using CRISPR-Cas9. TEAD1 ablation robustly diminishes migration, both in vitro and in vivo, and alters migratory and EMT transcriptome signatures with consistent downregulation of its target AQP4. TEAD1 overexpression restores AQP4 expression, and both TEAD1 and AQP4 overexpression rescue migratory deficits in TEAD1-knockout cells, implicating a direct regulatory role for TEAD1-AQP4 in GBM migration.
2018-07-27 | GSE117685 | GEO
Project description:The intrinsic drivers of migration in glioblastoma (GBM) are poorly understood. To better capture the native molecular imprint of GBM and its developmental context, here we isolate human stem cell populations from GBM (GSC) and germinal matrix tissues and map their chromatin accessibility via ATAC-seq. We uncover two distinct regulatory GSC signatures, a developmentally shared/proliferative and a tumor-specific/migratory one in which TEAD1/4 motifs are uniquely overrepresented. Using ChIP-PCR, we validate TEAD1 trans occupancy at accessibility sites within AQP4, EGFR, and CDH4. To further characterize TEAD's functional role in GBM, we knockout TEAD1 or TEAD4 in patient-derived GBM lines using CRISPR-Cas9. TEAD1 ablation robustly diminishes migration, both in vitro and in vivo, and alters migratory and EMT transcriptome signatures with consistent downregulation of its target AQP4. TEAD1 overexpression restores AQP4 expression, and both TEAD1 and AQP4 overexpression rescue migratory deficits in TEAD1-knockout cells, implicating a direct regulatory role for TEAD1-AQP4 in GBM migration.
| S-EPMC6167382 | biostudies-literature
Project description:Glioblastoma cells are characterized by a highly invasive behavior whose mechanisms are not yet understood. Using the wound healing and Boyden chamber assays we compared in the present study the migration and invasion abilities of 5 glioblastoma cell lines (DK-MG, GaMG, U87-MG, U373-MG, SNB19) differing in p53 and PTEN status. We also analyzed by Western blotting the expression of PTEN, p53, mTOR and several other marker proteins involved in cell adhesion, migration and invasion. Among 5 cell lines, GaMG cells exhibited the fastest rate of wound closure, whereas U87-MG cells showed the most rapid chemotactic migration in the Boyden chamber assay. In DK-MG and GaMG cells, F-actin mainly occurred in the numerous stress fibers spanning the cytoplasm, whereas U87-MG, U373-MG and SNB19 cells preferentially expressed F-actin in filopodia and lamellipodia. Moreover, the two glioblastoma lines mutated in both p53 and PTEN genes (U373-MG and SNB19) were found to exhibit the fastest invasion rates through the Matrigel matrix. Here, we performed a gene expression profiling of the five glioblastoma cell lines to examine the molecular framework of differences in invasive behavior to find possible targets for chemo- and radiation therapy.
2014-09-05 | E-GEOD-53124 | biostudies-arrayexpress
Project description:It is currently challenging to adequately model the growth and migration of glioblastoma using 2D in vitro culture systems as they quickly lose the original, patient-specific identity and heterogeneity. However, with the advent of 3D cell cultures and human induced pluripotent stem cells (iPSCs)-derived cerebral organoids (COs), studies demonstrate that the glioblastoma-cerebral organoid (GLICO) co-culture model helps to preserve the phenotype of the patient-specific tissue. Here we aimed to set up such a model using mature COs and develop a pipeline for subsequent analysis of co-cultured glioblastoma. Our data demonstrates that the growth and migration of the glioblastoma cell line within the mature COs are significantly increased in the presence of extracellular matrix proteins, shortening the time needed for glioblastoma to initiate migration. We also describe in detail the method for the visualization and quantification of these migrating cells within the GLICO model. Lastly, we show that this co-culture model (and the human brain-like microenvironment) can significantly transform the gene expression profile of the established U87 glioblastoma cell line into proneural and classical glioblastoma cell types.
2023-02-22 | GSE216626 | GEO
Project description:Glioblastoma is the most frequent and aggressive primary astrocytoma in adults. The high migration ability of the tumor cells is an important reason for the high recurrence rate and poor prognosis of glioblastoma. Recently, emerging evidence has shown that the migration ability of glioblastoma cell was inhibited upon the activation of aryl hydrocarbon receptor (AhR), suggesting potential anti-tumor effects of AhR agonists. Rutaecarpine is a natural compound with potential tumor therapeutic effects which can possibly bind to AhR. However, its effect on the migration of glioblastoma is unclear. Therefore, we aim to explore the effects of rutaecarpine on the migration of human glioblastoma cells U87 and the involvements of the AhR signaling pathway. The results showed that: (i) compared with other structural related alkaloids, like evodiamine and dehydroevodiamine, rutaecarpine was a more potent AhR activator, and has stronger inhibitory effect on the glioblastoma cell migration; (ii) rutaecarpine decreased the migration ability of U87 cells in an AhR-dependent manner; (iii) AhR mediated the expression of a tumor suppressor interleukin 24 (IL24) induced by rutaecarpine, and AhR-IL24 axis was involved in the anti-migratoryeffects of rutaecarpine on the glioblastoma. Besides IL24, other motility related genes were proposed to participate in the migration regulation process of rutaecarpine by RNA-Seq analysis. These data suggest that rutaecarpine is a natural AhR agonist that could inhibit the migration of glioblastomaandbe a potential candidate for developing therapeutic drug against glioblatoma.
2021-12-07 | GSE183606 | GEO
Project description:Glioblastoma cells are characterized by a highly invasive behavior whose mechanisms are not yet understood. Using the wound healing and Boyden chamber assays we compared in the present study the migration and invasion abilities of 5 glioblastoma cell lines (DK-MG, GaMG, U87-MG, U373-MG, SNB19) differing in p53 and PTEN status. We also analyzed by Western blotting the expression of PTEN, p53, mTOR and several other marker proteins involved in cell adhesion, migration and invasion. Among 5 cell lines, GaMG cells exhibited the fastest rate of wound closure, whereas U87-MG cells showed the most rapid chemotactic migration in the Boyden chamber assay. In DK-MG and GaMG cells, F-actin mainly occurred in the numerous stress fibers spanning the cytoplasm, whereas U87-MG, U373-MG and SNB19 cells preferentially expressed F-actin in filopodia and lamellipodia. Moreover, the two glioblastoma lines mutated in both p53 and PTEN genes (U373-MG and SNB19) were found to exhibit the fastest invasion rates through the Matrigel matrix.
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Project description:Human cytomegalovirus (HCMV) infects up to 80% of the world’s population and is linked to serious morbidity in immunocompromised individuals and newborns. Here, using multiple genome-scale assays and computational approaches, we show that HCMV infection leads to widespread changes in chromatin accessibility and chromatin looping, with hundreds of thousands of human genomic regions affected 48 hours after infection. Integrative analyses reveal that HCMV infection perturbs the Hippo signaling pathway by drastically diminishing TEA domain transcription factor 1 (TEAD1) activity. Chromatin immunoprecipitation experiments confirm extensive concordant loss of TEAD1 binding and H3K27ac active histone marks upon infection. TEAD transcription factors are direct effectors of the Hippo signaling pathway, and our data support a position for TEAD1 at the top of a hierarchy involving key developmental pathways with differential expression subsequent to HMCV infection. Known gene targets of TEAD1, including Cellular Communication Network Factor 1 (CCN1) and Thrombospondin 1 (THBS1), are significantly downregulated with HCMV infection, reflecting diminished TEAD1-mediated activity. HCMV infection reduces TEAD1 binding through four distinct mechanisms: closing of TEAD1-bound chromatin, reduction of Yes1 associated transcriptional regulator (YAP1) and phosphorylated YAP (pYAP1) levels, reduction of TEAD1 transcript and protein levels, and alteration of TEAD1 exon-6 usage. Collectively, these comprehensive genome-scale analyses reveal novel mechanisms induced by HCMV infection.
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Project description:TEAD1 acts as a key molecule of muscle development, and trans-activates multiple target genes involved in cell proliferation and differentiation pathways. However, its target genes in skeletal muscles, regulatory mechanisms and networks are unknown. Here, we use ChIP-on-chip to identify direct target genes of TEAD1. All animal procedures were performed according to protocols approved by Hubei Province, P. R. China for Biological Studies Animal Care and Use Committee. Skeletal muscle tissues were collected from three adult Kunming mice.
2011-02-01 | E-GEOD-26107 | biostudies-arrayexpress
Project description:Human cytomegalovirus (HCMV) infects up to 80% of the world’s population and is linked to serious morbidity in immunocompromised individuals and newborns. Here, using multiple genome-scale assays and computational approaches, we show that HCMV infection leads to widespread changes in chromatin accessibility and chromatin looping, with hundreds of thousands of human genomic regions affected 48 hours after infection. Integrative analyses reveal that HCMV infection perturbs the Hippo signaling pathway by drastically diminishing TEA domain transcription factor 1 (TEAD1) activity. Chromatin immunoprecipitation experiments confirm extensive concordant loss of TEAD1 binding and H3K27ac active histone marks upon infection. TEAD transcription factors are direct effectors of the Hippo signaling pathway, and our data support a position for TEAD1 at the top of a hierarchy involving key developmental pathways with differential expression subsequent to HMCV infection. Known gene targets of TEAD1, including Cellular Communication Network Factor 1 (CCN1) and Thrombospondin 1 (THBS1), are significantly downregulated with HCMV infection, reflecting diminished TEAD1-mediated activity. HCMV infection reduces TEAD1 binding through four distinct mechanisms: closing of TEAD1-bound chromatin, reduction of Yes1 associated transcriptional regulator (YAP1) and phosphorylated YAP (pYAP1) levels, reduction of TEAD1 transcript and protein levels, and alteration of TEAD1 exon-6 usage. Collectively, these comprehensive genome-scale analyses reveal novel mechanisms induced by HCMV infection.
2024-12-06 | GSE254736 | GEO
Project description:Human cytomegalovirus (HCMV) infects up to 80% of the world’s population and is linked to serious morbidity in immunocompromised individuals and newborns. Here, using multiple genome-scale assays and computational approaches, we show that HCMV infection leads to widespread changes in chromatin accessibility and chromatin looping, with hundreds of thousands of human genomic regions affected 48 hours after infection. Integrative analyses reveal that HCMV infection perturbs the Hippo signaling pathway by drastically diminishing TEA domain transcription factor 1 (TEAD1) activity. Chromatin immunoprecipitation experiments confirm extensive concordant loss of TEAD1 binding and H3K27ac active histone marks upon infection. TEAD transcription factors are direct effectors of the Hippo signaling pathway, and our data support a position for TEAD1 at the top of a hierarchy involving key developmental pathways with differential expression subsequent to HMCV infection. Known gene targets of TEAD1, including Cellular Communication Network Factor 1 (CCN1) and Thrombospondin 1 (THBS1), are significantly downregulated with HCMV infection, reflecting diminished TEAD1-mediated activity. HCMV infection reduces TEAD1 binding through four distinct mechanisms: closing of TEAD1-bound chromatin, reduction of Yes1 associated transcriptional regulator (YAP1) and phosphorylated YAP (pYAP1) levels, reduction of TEAD1 transcript and protein levels, and alteration of TEAD1 exon-6 usage. Collectively, these comprehensive genome-scale analyses reveal novel mechanisms induced by HCMV infection.
2024-12-06 | GSE254735 | GEO