Divergence from the human astrocyte developmental trajectory in glioblastoma [hMe-Seal-seq]
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ABSTRACT:
PROVIDER: PRJNA1154689 | ENA |
REPOSITORIES: ENA
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Project description:Glioblastoma (GBM) is defined by heterogenous and resilient cell populations that closely reflect neurodevelopmental cell types. While it is clear that GBM echoes early and immature cell states, identifying the specific developmental programs disrupted in these tumors has been hindered by a lack of high-resolution trajectories of glial and neuronal lineages. Here, we delineate the course of human astrocyte maturation to uncover discrete developmental stages and attributes mirrored by GBM. We generated a transcriptomic and epigenomic map of human astrocyte maturation using cortical organoids maintained in culture for nearly two years. Through this approach, we chronicled a multi-phase developmental process orchestrated by a series of transcription factor and gene regulatory networks. Our time course of human astrocyte maturation includes a novel and molecularly distinct intermediate period that serves as a lineage commitment checkpoint upstream of mature quiescence. This intermediate stage acts as a site of developmental deviation separating IDH-wildtype neoplastic astrocyte lineage cells from quiescent astrocyte populations. Interestingly, IDH1-mutant tumor astrocyte lineage cells are the exception to this developmental perturbation, where immature properties are suppressed as a result of D2HG oncometabolite exposure. We propose that this defiance is likely a consequence of IDH1mt-associated epigenetic dysregulation and we identified biased DNA hydroxymethylation (5hmC) in maturation genes as a possible mechanism. Together, this study illustrates a novel cellular state aberration in GBM astrocyte lineage cells and presents new developmental targets for experimental and therapeutic exploration.
2024-10-31 | GSE276102 | GEO
Project description:Divergence from the human astrocyte developmental trajectory in glioblastoma
| PRJNA1155637 | ENA
Project description:In the present study, we applied two whole-genome sequencing techniques (WGBS/oxBS and hMe-Seal) to detect 5hmC (and 5mC) changes during the differentiation of the human SGBS preadipocyte cell line to mature adipocytes. As technical and biological validation we performed BS and oxBS followed by 450k array analysis. RNA-seq data was performed in parallel to study transcriptional changes associated with differential hydroxymethylation. In human white adipose tissue (WAT) hydroxymethylation (hME-Seal) was characterized in comparison with histone modifications and acNEIL1 binding (ACT-seq).
2024-02-01 | GSE161110 | GEO
Project description:Divergence from the human astrocyte developmental trajectory in glioblastoma [MeDIP-seq]
| PRJNA1154690 | ENA
Project description:Divergence from the human astrocyte developmental trajectory in glioblastoma [bulk RNA]
| PRJNA1155638 | ENA
Project description:Divergence from the human astrocyte developmental trajectory in glioblastoma [bulk ATAC-seq]
| PRJNA1154688 | ENA
Project description:Although mechanisms underlying early steps in cerebellar development are known, evidence is lacking on genetic and epigenetic changes during the establishment of the synaptic circuitry. Using metagene analysis, we report pivotal changes in multiple reactomes of epigenetic pathway genes in cerebellar granule cells (GCs) during circuit formation. During this stage, Tet genes are up-regulated and vitamin C activation of Tet enzymes increases the levels of 5-hydroxymethylcytosine (5hmC) at exon start sites of up-regulated genes, notably axon guidance genes and ion channel genes. Knockdown of Tet1 and Tet3 by RNA interference in ex vivo cerebellar slice cultures inhibits dendritic arborization of developing GCs, a critical step in circuit formation. These findings demonstrate a role for Tet genes and chromatin remodeling genes in the formation of cerebellar circuitry. 5hmC-enriched genomic DNA fragments were purified with a selective labeling strategy known as hMe-Seal and carried out DNA deep sequencing using Illumina HiSeq 2500.
2015-10-31 | E-GEOD-74401 | biostudies-arrayexpress
Project description:Glioblastoma (GBM) is defined by heterogenous and resilient cell populations that closely reflect neurodevelopmental cell types. While it is clear that GBM echoes early and immature cell states, identifying the specific developmental programs disrupted in these tumors has been hindered by a lack of high-resolution trajectories of glial and neuronal lineages. Here, we delineate the course of human astrocyte maturation to uncover discrete developmental stages and attributes mirrored by GBM. We generated a transcriptomic and epigenomic map of human astrocyte maturation using cortical organoids maintained in culture for nearly two years. Through this approach, we chronicled a multi-phase developmental process orchestrated by a series of transcription factor and gene regulatory networks. Our time course of human astrocyte maturation includes a novel and molecularly distinct intermediate period that serves as a lineage commitment checkpoint upstream of mature quiescence. This intermediate stage acts as a site of developmental deviation separating IDH-wildtype neoplastic astrocyte lineage cells from quiescent astrocyte populations. Interestingly, IDH1-mutant tumor astrocyte lineage cells are the exception to this developmental perturbation, where immature properties are suppressed as a result of D2HG oncometabolite exposure. We propose that this defiance is likely a consequence of IDH1mt-associated epigenetic dysregulation and we identified biased DNA hydroxymethylation (5hmC) in maturation genes as a possible mechanism. Together, this study illustrates a novel cellular state aberration in GBM astrocyte lineage cells and presents new developmental targets for experimental and therapeutic exploration.
2024-10-31 | GSE276177 | GEO
Project description:Glioblastoma (GBM) is defined by heterogenous and resilient cell populations that closely reflect neurodevelopmental cell types. While it is clear that GBM echoes early and immature cell states, identifying the specific developmental programs disrupted in these tumors has been hindered by a lack of high-resolution trajectories of glial and neuronal lineages. Here, we delineate the course of human astrocyte maturation to uncover discrete developmental stages and attributes mirrored by GBM. We generated a transcriptomic and epigenomic map of human astrocyte maturation using cortical organoids maintained in culture for nearly two years. Through this approach, we chronicled a multi-phase developmental process orchestrated by a series of transcription factor and gene regulatory networks. Our time course of human astrocyte maturation includes a novel and molecularly distinct intermediate period that serves as a lineage commitment checkpoint upstream of mature quiescence. This intermediate stage acts as a site of developmental deviation separating IDH-wildtype neoplastic astrocyte lineage cells from quiescent astrocyte populations. Interestingly, IDH1-mutant tumor astrocyte lineage cells are the exception to this developmental perturbation, where immature properties are suppressed as a result of D2HG oncometabolite exposure. We propose that this defiance is likely a consequence of IDH1mt-associated epigenetic dysregulation and we identified biased DNA hydroxymethylation (5hmC) in maturation genes as a possible mechanism. Together, this study illustrates a novel cellular state aberration in GBM astrocyte lineage cells and presents new developmental targets for experimental and therapeutic exploration.
2024-10-31 | GSE276176 | GEO
Project description:Glioblastoma (GBM) is defined by heterogenous and resilient cell populations that closely reflect neurodevelopmental cell types. While it is clear that GBM echoes early and immature cell states, identifying the specific developmental programs disrupted in these tumors has been hindered by a lack of high-resolution trajectories of glial and neuronal lineages. Here, we delineate the course of human astrocyte maturation to uncover discrete developmental stages and attributes mirrored by GBM. We generated a transcriptomic and epigenomic map of human astrocyte maturation using cortical organoids maintained in culture for nearly two years. Through this approach, we chronicled a multi-phase developmental process orchestrated by a series of transcription factor and gene regulatory networks. Our time course of human astrocyte maturation includes a novel and molecularly distinct intermediate period that serves as a lineage commitment checkpoint upstream of mature quiescence. This intermediate stage acts as a site of developmental deviation separating IDH-wildtype neoplastic astrocyte lineage cells from quiescent astrocyte populations. Interestingly, IDH1-mutant tumor astrocyte lineage cells are the exception to this developmental perturbation, where immature properties are suppressed as a result of D2HG oncometabolite exposure. We propose that this defiance is likely a consequence of IDH1mt-associated epigenetic dysregulation and we identified biased DNA hydroxymethylation (5hmC) in maturation genes as a possible mechanism. Together, this study illustrates a novel cellular state aberration in GBM astrocyte lineage cells and presents new developmental targets for experimental and therapeutic exploration.
2024-10-31 | GSE276103 | GEO