High SOX9 promotes glioma stem cell activity through a regulatory loop involving STAT3 and PML
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ABSTRACT:
PROVIDER: PRJNA750444 | ENA |
REPOSITORIES: ENA
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Project description:Point mutations in histone variant H3.3 (H3.3 K27M, H3.3 G34R) and the H3.3-specific ATRX/DAXX chaperone complex are frequent events in paediatric gliomas. It is clear that H3.3 point mutations affect many chromatin modifications but the exact oncogenic mechanisms are an area of active investigation. Histone H3.3 has been previously linked to PML, a gene which is frequently mutated in Acute Promyelocytic Leukaemia. We find that H3.3 point mutations disrupt the formation of PML nuclear bodies and this prevents differentiation down glial lineages. Similar to PML-mutated Acute Promyelocytic Leukaemias, H3.3-mutated patient-derived gliomas cells are also sensitive to drugs which target PML bodies. We identify PML as a contributor to oncogenesis in H3.3-mutated gliomas and our results indicate that PML-targeting strategies may prove effective at treating H3.3-mutated paediatric gliomas.
2023-11-19 | GSE210190 | GEO
Project description:The Pml gene is essential to the formation of PML nuclear bodies, domains which have been associated with various functions such as apoptosis/senescence, DNA repair and cell proliferation( Lallemand-Breitenbach 2010). PML-NBs formation is regulated by cellular stress including oxidative stress(Jeanne 2010, de The 2012). To investigate the role of PML in ROS response in vivo, we analyse the expression difference betweem Pml wt and Pml KO under fasted condition, which easily up-regulate ROS in BALB/cByJ background
2017-09-22 | GSE100615 | GEO
Project description:Transcription factor SOX9 is essential for the differentiation of chondrocytes and the development of testes. Heterozygous point mutations and genomic deletions involving SOX9 lead to campomelic dysplasia (CD) often associated with sex reversal. Chromosomal rearrangements with breakpoints mapping up to 1.3 Mb up- and downstream to SOX9, and likely disrupting its distant cis-regulatory elements, have been described in patients with milder forms of CD. Performing chromosome conformation capture-on-chip (4C) analysis in Sertoli cells and lymphoblasts we identified several novel potentially cis-interacting regions both up- and downstream to SOX9, with some of them overlapping lncRNA genes preferentially expressed in testes. Custom designed 3x720K tiling microarrays covering 4 Mb region (chr17:68,117,161-72,122,560) flanking SOX9 gene of interest
2013-09-08 | E-GEOD-50449 | biostudies-arrayexpress
Project description:The Pml gene is essential to the formation of PML nuclear bodies, domains which have been associated with various functions such as apoptosis/senescence, DNA repair and cell proliferation( Lallemand-Breitenbach 2010). PML-NBs formation is regulated by cellular stress including oxidative stress(Jeanne 2010, de The 2012). To investigate the role of PML in ROS response in vivo, we analyse the expression difference to the acetaminophen toxicity, which is initiated by ROS, in Pml wt and Pml KO mice.
2017-09-22 | GSE100616 | GEO
Project description:Because PML-RARA-positive acute promyelocytic leukemia (APL) is a morphologically differentiated leukemia, much speculation has been made about whether its leukemic cell of origin might be committed myeloid precursor (e.g., a promyelocyte) vs. a hematopoietic stem/progenitor cell (HSPC). We originally targeted PML-RARA expression with CTSG regulatory elements, based on the early observation that this gene was maximally expressed in cells with promyelocyte morphology. Here, we show that both Ctsg and PML-RARA targeted to the Ctsg locus (in Ctsg-PML-RARA mice) are detected in the purified KLS cells of these mice (Kit+Lin-Sca+ cells, which are highly enriched for HSPCs), and this expression results in biological effects in multi-lineage competitive repopulation assays. Although PML-RARA is indeed expressed at high levels in the promyelocytes of Ctsg-PML-RARA mice, it does not significantly alter the transcriptional signature of these cells, or induce their self-renewal. In sum, these results suggest that in murine models, PML-RARA acts primarily to affect the function of multi-potent progenitor cells, rather than promyelocytes. Since PML/Pml is normally expressed in the HSPCs of both humans and mice, and since some human APL samples contain TCR rearrangements and express T lineage genes, we suggest that the very early hematopoietic expression of PML-RARA in our mouse model may closely mimic the physiologic expression pattern of PML-RARA in human APL patients. Bone marrow from individual mice expressing PML-RARA from the murine Ctg locus (mCG-PR) and littermate controls was harvested from both femurs and tibia. Standard cell lysis was performed, and total RNA was extracted from the cells and analyzed using the Affymetrix Mouse Exon 1.0 ST platform.
2012-08-13 | E-GEOD-40022 | biostudies-arrayexpress
Project description:Because PML-RARA-positive acute promyelocytic leukemia (APL) is a morphologically differentiated leukemia, much speculation has been made about whether its leukemic cell of origin might be committed myeloid precursor (e.g., a promyelocyte) vs. a hematopoietic stem/progenitor cell (HSPC). We originally targeted PML-RARA expression with CTSG regulatory elements, based on the early observation that this gene was maximally expressed in cells with promyelocyte morphology. Here, we show that both Ctsg and PML-RARA targeted to the Ctsg locus (in Ctsg-PML-RARA mice) are detected in the purified KLS cells of these mice (Kit+Lin-Sca+ cells, which are highly enriched for HSPCs), and this expression results in biological effects in multi-lineage competitive repopulation assays. Although PML-RARA is indeed expressed at high levels in the promyelocytes of Ctsg-PML-RARA mice, it does not significantly alter the transcriptional signature of these cells, or induce their self-renewal. In sum, these results suggest that in murine models, PML-RARA acts primarily to affect the function of multi-potent progenitor cells, rather than promyelocytes. Since PML/Pml is normally expressed in the HSPCs of both humans and mice, and since some human APL samples contain TCR rearrangements and express T lineage genes, we suggest that the very early hematopoietic expression of PML-RARA in our mouse model may closely mimic the physiologic expression pattern of PML-RARA in human APL patients.
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Project description:Transcriptional profiling of murine cells expressing PML/RARA at the early promyelocyte stage (4 weeks old, preleukemic) and in full blown PML/RARA leukemia generated by transducing PML/RARA bone marrow with a Flt3-ITD retroviral vector
2015-07-15 | GSE59431 | GEO
Project description:The promyelocytic leukemia (PML) body is a phase-separated nuclear structure composed of various proteins including several chromatin regulators, and physically associates with chromatin. To address functional roles of the PML-chromatin association, we conducted genome-wide profiling of PML body-associated regions.
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Project description:Epigenetic dysregulation is a universal feature of cancer that results in altered patterns of gene expression that drive malignancy. Brain tumors exhibit subtype-specific epigenetic alterations, however the molecular mechanisms responsible for these diverse epigenetic states remain unclear. Here we show that the developmental transcription factor Sox9 differentially regulates epigenomic states in high-grade glioma (HGG) and ependymoma (EPN). These contrasting roles for Sox9 correspond with protein interactions with histone deacetylating complexes in HGG, and association with the Rela oncofusion in EPN. Together, our studies demonstrate how epigenomic states are differentially regulated in distinct subtypes of brain tumors, while revealing divergent roles for Sox9 in HGG and EPN tumorigenesis.
2022-07-13 | PXD033863 | Pride