GABAergic neuronal lineage development determines clinically actionable targets in diffuse hemispheric glioma, H3G34-mutant [ChIP-Seq]
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PROVIDER: PRJNA1135967 | ENA |
REPOSITORIES: ENA
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Project description:GABAergic neuronal lineage development determines clinically actionable targets in diffuse hemispheric glioma, H3G34-mutant [RNA-Seq]
| PRJNA1135968 | ENA
Project description:Diffuse hemispheric gliomas, H3G34R/V-mutant (DHG-H3G34), are uniformly lethal malignancies lacking targeted therapies. These gliomas uniquely originate from interneuronal precursor cells, and leveraging this interneuronal lineage origin for mechanistic and therapeutic insights is a pressing need. Here, we elucidate the cell state composition of DHG-H3G34, resolving a cellular hierarchy along continuous interneuron lineage development. In the developing human brain, interneuron lineage precursors form characteristic histological patterns organized in streams of progenitor cells surrounding nests of migratory interneurons, and we find these same spatial patterns to be mirrored in primary DHG-H3G34 tumors. We integrated these findings with genome-wide CRISPR-Cas9 screens, which revealed the majority of dependencies to be genes upregulated in interneuron lineage progenitors, highlighting these as a driver of DHG-H3G34. We validated the essentiality of these lineage-associated targets in patient-derived in vitro and in vivo models. Among these, CDK6 emerged as a targetable dependency, and we demonstrated enhanced sensitivity of DHG-H3G34 tumor cells to CDK4/6 inhibitors and a CDK6-specific degrader. Inhibition of CDK6 shifted cells towards more mature interneuron-like cell states, reduced tumor growth, and prolonged survival of patient-derived xenografts. Concordantly, a patient with progressive DHG-H3G34 under second line therapy was treated with a CDK4/6 inhibitor, and exhibited stable disease for 17 months. Collectively, we identify interneuronal progenitor-like states, organized in characteristic developmental spatial niches, as a distinct vulnerability consistently upregulated in DHG-H3G34 tumors, and provide initial evidence for CDK6 as a clinically actionable target particularly relevant for its interneuronal developmental biology.
2024-08-01 | GSE272262 | GEO
Project description:Diffuse hemispheric gliomas, H3G34R/V-mutant (DHG-H3G34), are uniformly lethal malignancies lacking targeted therapies. These gliomas uniquely originate from interneuronal precursor cells, and leveraging this interneuronal lineage origin for mechanistic and therapeutic insights is a pressing need. Here, we elucidate the cell state composition of DHG-H3G34, resolving a cellular hierarchy along continuous interneuron lineage development. In the developing human brain, interneuron lineage precursors form characteristic histological patterns organized in streams of progenitor cells surrounding nests of migratory interneurons, and we find these same spatial patterns to be mirrored in primary DHG-H3G34 tumors. We integrated these findings with genome-wide CRISPR-Cas9 screens, which revealed the majority of dependencies to be genes upregulated in interneuron lineage progenitors, highlighting these as a driver of DHG-H3G34. We validated the essentiality of these lineage-associated targets in patient-derived in vitro and in vivo models. Among these, CDK6 emerged as a targetable dependency, and we demonstrated enhanced sensitivity of DHG-H3G34 tumor cells to CDK4/6 inhibitors and a CDK6-specific degrader. Inhibition of CDK6 shifted cells towards more mature interneuron-like cell states, reduced tumor growth, and prolonged survival of patient-derived xenografts. Concordantly, a patient with progressive DHG-H3G34 under second line therapy was treated with a CDK4/6 inhibitor, and exhibited stable disease for 17 months. Collectively, we identify interneuronal progenitor-like states, organized in characteristic developmental spatial niches, as a distinct vulnerability consistently upregulated in DHG-H3G34 tumors, and provide initial evidence for CDK6 as a clinically actionable target particularly relevant for its interneuronal developmental biology.
2024-08-01 | GSE272261 | GEO
Project description:As part of a multi-omics and CRISPR/Cas9-screen based study to extensively characterize the molecular basis of diffuse hemispheric gliomas, H3G34-mutant (DHG-H3G34), we applied single-cell/single-nucleus RNA-sequencing to a patient cohort of 9 fresh and frozen untreated DHG-H3G34.
2024-07-30 | GSE162989 | GEO
Project description:Background Hemispheric asymmetry in neuronal processes is a fundamental feature of the human brain and drives symptom lateralization in Parkinson's disease (PD), but its molecular determinants are unknown. Here, we identify divergent epigenetic patterns involved in hemispheric asymmetry by profiling DNA methylation in isolated prefrontal cortex neurons from control and PD brain hemispheres. DNA methylation is fine-mapped at enhancers and promoters, genome-wide, by targeted bisulfite sequencing in two independent sample cohorts. Results We find that neurons of the human prefrontal cortex exhibit hemispheric differences in DNA methylation. Hemispheric asymmetry in neuronal DNA methylation patterns is largely mediated by differential CpH methylation, and chromatin conformation analysis finds that it targets thousands of genes. With aging, there is a loss of hemispheric asymmetry in neuronal epigenomes, such that hemispheres epigenetically converge in late life. In neurons of PD patients, hemispheric asymmetry in DNA methylation is greater than in controls and involves many PD risk genes. Epigenetic, transcriptomic, and proteomic differences between PD hemispheres correspond to the lateralization of PD symptoms, with abnormalities being most prevalent in the hemisphere matched to side of symptom predominance. Hemispheric asymmetry and symptom lateralization in PD is linked to genes affecting neurodevelopment, immune activation, and synaptic transmission. PD patients with a long disease course have greater hemispheric asymmetry in neuronal epigenomes than those with a short disease course. Conclusions Hemispheric differences in epigenetic gene regulation are prevalent in neurons and may affect the progression and symptoms of PD.
2020-02-12 | GSE135037 | GEO
Project description:Background Hemispheric asymmetry in neuronal processes is a fundamental feature of the human brain and drives symptom lateralization in Parkinson's disease (PD), but its molecular determinants are unknown. Here, we identify divergent epigenetic patterns involved in hemispheric asymmetry by profiling DNA methylation in isolated prefrontal cortex neurons from control and PD brain hemispheres. DNA methylation is fine-mapped at enhancers and promoters, genome-wide, by targeted bisulfite sequencing in two independent sample cohorts. Results We find that neurons of the human prefrontal cortex exhibit hemispheric differences in DNA methylation. Hemispheric asymmetry in neuronal DNA methylation patterns is largely mediated by differential CpH methylation, and chromatin conformation analysis finds that it targets thousands of genes. With aging, there is a loss of hemispheric asymmetry in neuronal epigenomes, such that hemispheres epigenetically converge in late life. In neurons of PD patients, hemispheric asymmetry in DNA methylation is greater than in controls and involves many PD risk genes. Epigenetic, transcriptomic, and proteomic differences between PD hemispheres correspond to the lateralization of PD symptoms, with abnormalities being most prevalent in the hemisphere matched to side of symptom predominance. Hemispheric asymmetry and symptom lateralization in PD is linked to genes affecting neurodevelopment, immune activation, and synaptic transmission. PD patients with a long disease course have greater hemispheric asymmetry in neuronal epigenomes than those with a short disease course. Conclusions Hemispheric differences in epigenetic gene regulation are prevalent in neurons and may affect the progression and symptoms of PD.
2020-02-12 | GSE135035 | GEO
Project description:Background Hemispheric asymmetry in neuronal processes is a fundamental feature of the human brain and drives symptom lateralization in Parkinson's disease (PD), but its molecular determinants are unknown. Here, we identify divergent epigenetic patterns involved in hemispheric asymmetry by profiling DNA methylation in isolated prefrontal cortex neurons from control and PD brain hemispheres. DNA methylation is fine-mapped at enhancers and promoters, genome-wide, by targeted bisulfite sequencing in two independent sample cohorts. Results We find that neurons of the human prefrontal cortex exhibit hemispheric differences in DNA methylation. Hemispheric asymmetry in neuronal DNA methylation patterns is largely mediated by differential CpH methylation, and chromatin conformation analysis finds that it targets thousands of genes. With aging, there is a loss of hemispheric asymmetry in neuronal epigenomes, such that hemispheres epigenetically converge in late life. In neurons of PD patients, hemispheric asymmetry in DNA methylation is greater than in controls and involves many PD risk genes. Epigenetic, transcriptomic, and proteomic differences between PD hemispheres correspond to the lateralization of PD symptoms, with abnormalities being most prevalent in the hemisphere matched to side of symptom predominance. Hemispheric asymmetry and symptom lateralization in PD is linked to genes affecting neurodevelopment, immune activation, and synaptic transmission. PD patients with a long disease course have greater hemispheric asymmetry in neuronal epigenomes than those with a short disease course. Conclusions Hemispheric differences in epigenetic gene regulation are prevalent in neurons and may affect the progression and symptoms of PD.
2020-02-12 | GSE145153 | GEO
Project description:Background Hemispheric asymmetry in neuronal processes is a fundamental feature of the human brain and drives symptom lateralization in Parkinson's disease (PD), but its molecular determinants are unknown. Here, we identify divergent epigenetic patterns involved in hemispheric asymmetry by profiling DNA methylation in isolated prefrontal cortex neurons from control and PD brain hemispheres. DNA methylation is fine-mapped at enhancers and promoters, genome-wide, by targeted bisulfite sequencing in two independent sample cohorts. Results We find that neurons of the human prefrontal cortex exhibit hemispheric differences in DNA methylation. Hemispheric asymmetry in neuronal DNA methylation patterns is largely mediated by differential CpH methylation, and chromatin conformation analysis finds that it targets thousands of genes. With aging, there is a loss of hemispheric asymmetry in neuronal epigenomes, such that hemispheres epigenetically converge in late life. In neurons of PD patients, hemispheric asymmetry in DNA methylation is greater than in controls and involves many PD risk genes. Epigenetic, transcriptomic, and proteomic differences between PD hemispheres correspond to the lateralization of PD symptoms, with abnormalities being most prevalent in the hemisphere matched to side of symptom predominance. Hemispheric asymmetry and symptom lateralization in PD is linked to genes affecting neurodevelopment, immune activation, and synaptic transmission. PD patients with a long disease course have greater hemispheric asymmetry in neuronal epigenomes than those with a short disease course. Conclusions Hemispheric differences in epigenetic gene regulation are prevalent in neurons and may affect the progression and symptoms of PD.
2020-02-12 | GSE135036 | GEO
Project description:hiPSC-derived bone marrow milieu identifies a clinically actionable driver of niche-mediated treatment resistance in leukemia
| PRJNA858088 | ENA
Project description:Single-cell/single-nucleus RNA-seq of diffuse hemispheric gliomas, H3G34-mutant.
| PRJNA684143 | ENA