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Rapid PTEFb-dependent transcriptional reorganization underpins the glioma adaptive response to radiotherapy [ATAC-Seq]

ABSTRACT: Using a combination of ChIP-, ATAC-, RNA-seq, and CUT&RUN in model systems of diffuse intrinsic pontine glioma and other pediatric high-grade gliomas, we observe a rapid genome-wide reorganization of active chromatin within hours of exposure to therapeutic ionizing radiation. This redistribution facilitates PTEFb-mediated pause-release of Pol II to drive nascent transcriptional induction of canonical DNA damage response programs. Concurrent inhibition of PTEFb imparts a transcription elongation defect, disrupting this chromatin reorganization and blunting transcriptional induction. Functionally, concurrent PTEFb inhibition abrogates key adaptive programs such as DNA damage repair and cell cycle regulation. This combination demonstrates a potent, synergistic therapeutic potential agnostic of glioma subtype, leading to a marked induction of tumor cell apoptosis and prolongation of xenograft survival.

ORGANISM(S): Homo sapiens

PROVIDER: GSE227792 | GEO | 2024/04/12

REPOSITORIES: GEO

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Rapid PTEFb-dependent transcriptional reorganization underpins the glioma adaptive response to radiotherapy [CUT&RUN]

Project description:Using a combination of ChIP-, ATAC-, and RNA-seq in model systems of diffuse intrinsic pontine glioma and other pediatric high-grade gliomas, we observe a rapid genome-wide reorganization of active chromatin within hours of exposure to therapeutic ionizing radiation. This redistribution facilitates PTEFb-mediated pause-release of Pol II to drive nascent transcriptional induction of canonical DNA damage response programs. Concurrent inhibition of PTEFb imparts a transcription elongation defect, disrupting this chromatin reorganization and blunting transcriptional induction. Functionally, concurrent PTEFb inhibition abrogates key adaptive programs such as DNA damage repair and cell cycle regulation. This combination demonstrates a potent, synergistic therapeutic potential agnostic of glioma subtype, leading to a marked induction of tumor cell apoptosis and prolongation of xenograft survival.

2024-04-15 | GSE227795 | GEO

Rapid PTEFb-dependent transcriptional reorganization underpins the glioma adaptive response to radiotherapy [ChIP-Seq]

Project description:Using a combination of ChIP-, ATAC-, RNA-seq, and CUT&RUN in model systems of diffuse intrinsic pontine glioma and other pediatric high-grade gliomas, we observe a rapid genome-wide reorganization of active chromatin within hours of exposure to therapeutic ionizing radiation. This redistribution facilitates PTEFb-mediated pause-release of Pol II to drive nascent transcriptional induction of canonical DNA damage response programs. Concurrent inhibition of PTEFb imparts a transcription elongation defect, disrupting this chromatin reorganization and blunting transcriptional induction. Functionally, concurrent PTEFb inhibition abrogates key adaptive programs such as DNA damage repair and cell cycle regulation. This combination demonstrates a potent, synergistic therapeutic potential agnostic of glioma subtype, leading to a marked induction of tumor cell apoptosis and prolongation of xenograft survival.

2024-04-15 | GSE227796 | GEO

Rapid PTEFb-dependent transcriptional reorganization underpins the glioma adaptive response to radiotherapy [RNA-seq]

2024-04-16 | GSE263946 | GEO

Rapid PTEFb-dependent transcriptional reorganization underpins the glioma adaptive response to radiotherapy [ATAC-Seq]

Project description:This study examines the reorganization of transcriptionally active chromatin that underlies the adaptive response of glioblastoma cells to radiotherapy.

2023-12-01 | GSE211148 | GEO

Rapid PTEFb-dependent transcriptional reorganization underpins the glioma adaptive response to radiotherapy [ChIP-Seq]

Project description:This study examines the reorganization of transcriptionally active chromatin that underlies the adaptive response of glioblastoma cells to radiotherapy.

2023-12-01 | GSE211147 | GEO

Distinct layers of BRD4-PTEFb reveal bromodomain-independent function in transcriptional regulation

Project description:The BET family protein BRD4, which forms the CDK9-containing BRD4-PTEFb complex, is considered to be a master regulator of RNA polymerase II (Pol II) pause release. Because its tandem bromodomains interact with acetylated histone lysine residues, it has long been thought that BRD4 requires these bromodomains for its recruitment to chromatin and transcriptional regulatory function. Here, using rapid depletion and genetic complementation with domain deletion mutants, we demonstrate that BRD4 bromodomains are dispensable for Pol II pause release. A minimal, bromodomain-less C-terminal BRD4 fragment containing the PTEFb-interacting C-terminal motif (CTM) is instead both necessary and sufficient to mediate Pol II pause release in the absence of full-length BRD4. Although BRD4-PTEFb can associate with chromatin through acetyl recognition, our results indicate that a distinct, active BRD4-PTEFb population functions to regulate transcription independently of bromodomain-mediated chromatin association. These findings may enable more effective pharmaceutical modulation of BRD4-PTEFb activity.

2023-07-14 | GSE232869 | GEO

Rapid PTEFb-dependent transcriptional reorganization underpins the glioma adaptive response to radiotherapy

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

2024-04-12 | GSE227797 | GEO

Rapid PTEFb-dependent transcriptional reorganization underpins the glioma adaptive response to radiotherapy

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

2023-12-01 | GSE211149 | GEO

A cell state specific metabolic vulnerability to GPX4-dependent ferroptosis in glioblastoma

Project description:Glioma cells hijack developmental transcriptional programs to control cell state. During neural development, lineage trajectories rely on specialized metabolic pathways. However, the link between tumor cell state and metabolic programs is poorly understood in glioma. Here we uncover a glioma cell state-specific metabolic liability that can be leveraged therapeutically. To model the diversity of glioma cell states, we generated genetically-engineered murine gliomas, induced by deletion of p53 alone (p53) or with constitutively active Notch signaling (N1IC), a pathway critical in controlling CNS cell fate. N1IC tumors harbored quiescent astrocyte-like transformed cell states while p53 tumors were comprised of proliferating progenitor-like cell states. N1IC cells exhibit distinct metabolic alterations, with mitochondrial uncoupling and increased ROS production rendering them more sensitive to inhibition of the lipid hydroperoxidase GPX4 and induction of ferroptosis. Importantly, treating patient-derived organotypic slices with a GPX4 inhibitor induced selective depletion of quiescent AC-like glioma cell populations with similar metabolic profiles.

2023-08-16 | GSE224727 | GEO

Project description:Concurrent stem- and lineage-affiliated chromatin programs precede hematopoietic lineage restriction

| PRJNA625393 | ENA

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