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Dual targeting of processive transcription for Myc-driven circuitry in medulloblastoma [CUT&RUN]

ABSTRACT: Dual targeting of processive transcription for Myc-driven circuitry in medulloblastoma [CUT&RUN]

PROVIDER: PRJNA1111557 | ENA |

REPOSITORIES: ENA

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Dual targeting of processive transcription for Myc-driven circuitry in medulloblastoma

Project description:Dual targeting of processive transcription for Myc-driven circuitry in medulloblastoma

| PRJNA1111545 | ENA

Dual targeting of processive transcription for Myc-driven circuitry in medulloblastoma [CUT&RUN]

Project description:Medulloblastoma is the most common malignant brain tumor of childhood. The highest-risk tumors are driven by recurrent Myc amplifications (Myc-MB) and experience poorer outcomes despite intensive multimodal therapy. The Myc transcription factor defines core regulatory circuitry for these tumors and acts to broadly amplify downstream pro-survival transcriptional programs. Therapeutic targeting of Myc directly has proven elusive, but inhibiting transcriptional cofactors may present an indirect means of drugging the oncogenic transcriptional circuitry sustaining Myc-MB. Independent CRISPR-Cas9 screens were pooled to identify conserved dependencies in Myc-MB. We performed chromatin conformation capture (Hi-C) from primary patient Myc-MB samples to map enhancer-promoter interactions. We then treated in vitro and xenograft models with the dual CDK9/7 inhibitor zotiraciclib to evaluate effect on Myc-driven programs and tumor growth. Eight CRISPR-Cas9 screens performed across three independent labs identify CDK9 as a conserved dependency in Myc-MB. Myc-MB cells are susceptible to CDK9 inhibition, which is synergistic with concurrent inhibition of CDK7. The dual CDK9/7 inhibitor zotiraciclib disrupts enhancer-promoter activity in Myc-MB and downregulates Myc-driven transcriptional programs, exerting potent anti-tumor effect.

2024-11-14 | GSE267470 | GEO

Dual targeting of processive transcription for Myc-driven circuitry in medulloblastoma [Hi-C]

Project description:Dual targeting of processive transcription for Myc-driven circuitry in medulloblastoma [Hi-C]

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Dual targeting of processive transcription for Myc-driven circuitry in medulloblastoma [RNA-seq]

Project description:Dual targeting of processive transcription for Myc-driven circuitry in medulloblastoma [RNA-seq]

| PRJNA1111558 | ENA

Dual targeting of processive transcription for Myc-driven circuitry in medulloblastoma [Hi-C]

2024-11-14 | GSE267471 | GEO

Dual targeting of processive transcription for Myc-driven circuitry in medulloblastoma [RNA-seq]

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Dual targeting of processive transcription for Myc-driven circuitry in medulloblastoma

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-11-14 | GSE267473 | GEO

Hijacking a neurodevelopmental epigenomic program in metastatic dissemination of medulloblastoma [Cut & Run]

Project description:Hijacking a neurodevelopmental epigenomic program in metastatic dissemination of medulloblastoma [Cut & Run]

| PRJNA799749 | ENA

Expression profiling of human medulloblastoma cell line ONS76 upon siRNA-mediated knockdown of KDM5A/LSD1

Project description:KDM5A/LSD1 is an important epigenetic regulator in medulloblastoma, the most frequent brain tumor of childhood. Here, the response of ONS76 medulloblastoma cells upon siRNA-mediated knockdown of KDM5A is analysed. The expression profile of ONS76 cells upon KDM5A knockdown was compared to mock control. Both conditions were run in triplicate.

2013-08-01 | E-GEOD-43552 | biostudies-arrayexpress

O-GlcNAcylation Promotes Cerebellum Development and Medulloblastoma Oncogenesis via SHH Signaling

Project description:Sonic hedgehog (Shh) signaling plays a critical role in regulating cerebellum development by maintaining the physiological proliferation of granule neuron precursors (GNPs), and its dysregulation leads to the oncogenesis of medulloblastoma. O-GlcNAcylation (O-GlcNAc) of proteins is an emerging regulator of brain function that maintains normal development and neuronal circuitry. Here, we demonstrate that O-GlcNAc transferase (OGT) in GNPs mediate the cerebellum development, and the progression of the Shh-subgroup of medulloblastoma. Specifically, OGT regulates the proliferation of GNPs by activating the Shh signaling pathway via O-GlcNAcylation at S355 of GLI family zinc finger 2 (Gli2), which in turn promotes its deacetylation and transcriptional activity via dissociation from p300, a histone acetyltransferases (HATs). Inhibition of OGT via genetic ablation or chemical inhibition improves survival in a medulloblastoma mouse model. These data uncover a critical role for O-GlcNAc signaling in cerebellar development, and pinpoint a potential therapeutic target for Shh-associated medulloblastoma.

2022-06-02 | PXD034270 |

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