Dissection of the MEF2D-IRF8 transcriptional circuit dependency in acute myeloid leukemia
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA772709 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR16481314.fastq.gz | Fastqsanger.gz | |||
| SRR16481315.fastq.gz | Fastqsanger.gz | |||
| SRR16481316.fastq.gz | Fastqsanger.gz | |||
| SRR16481317.fastq.gz | Fastqsanger.gz | |||
| SRR16481318.fastq.gz | Fastqsanger.gz |
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Project description:Transcriptional dysregulation is a prominent feature in leukemia. Here, we systematically surveyed the transcription factor (TF) vulnerabilities in leukemia, and uncovered TF clusters that exhibit context-specific addictions within and between different subtypes of leukemia. We focused on and validated MEF2D as a requirement exclusively in AML with high IRF8 expression. Transcriptomic and chromatin-binding profiling revealed a key TF circuit composed of MEF2D-IRF8 vital for AML maintenance. AML can acquire dependence on this circuit through various mechanisms, including enhancer activation of the circuit via MLL-rearrangement. IRF8 cooperates with PU.1 to control PU.1/MEIS1 co-regulated transcriptional outputs, meanwhile coordinating with MEF2D to directly regulate genes in a non-redundant manner. Collectively, our study nominates a TF circuit in support of the pathogenesis of AML.
2022-09-07 | GSE186130 | GEO
Project description:Transcriptional dysregulation is a prominent feature in leukemia. Here, we systematically surveyed the transcription factor (TF) vulnerabilities in leukemia, and uncovered TF clusters that exhibit context-specific addictions within and between different subtypes of leukemia. We focused on and validated MEF2D as a requirement exclusively in AML with high IRF8 expression. Transcriptomic and chromatin-binding profiling revealed a key TF circuit composed of MEF2D-IRF8 vital for AML maintenance. AML can acquire dependence on this circuit through various mechanisms, including enhancer activation of the circuit via MLL-rearrangement. IRF8 cooperates with PU.1 to control PU.1/MEIS1 co-regulated transcriptional outputs, meanwhile coordinating with MEF2D to directly regulate genes in a non-redundant manner. Collectively, our study nominates a TF circuit in support of the pathogenesis of AML.
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Project description:Dissection of the MEF2D-IRF8 transcriptional circuit dependency in acute myeloid leukemia [CUT&RUN]
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Project description:Dissection of the MEF2D-IRF8 transcriptional circuit dependency in acute myeloid leukemia [ChIP-seq]
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Project description:Transcriptional dysregulation is a prominent feature in leukemia. Here, we systematically surveyed transcription factor (TF) vulnerabilities in leukemia and uncovered TF clusters that exhibit context-specific vulnerabilities within and between different subtypes of leukemia. Among these TF clusters, we demonstrated that acute myeloid leukemia (AML) with high IRF8 expression was addicted to MEF2D. MEF2D and IRF8 form an autoregulatory loop via direct binding to mutual enhancer elements. One important function of this circuit in AML is to sustain PU.1/MEIS1 co-regulated transcriptional outputs via stabilizing PU.1's chromatin occupancy. We illustrated that AML could acquire dependency on this circuit through various oncogenic mechanisms that results in the activation of their enhancers. In addition to forming a circuit, MEF2D and IRF8 can also separately regulate gene expression, and dual perturbation of these two TFs leads to a more robust inhibition of AML proliferation. Collectively, our results revealed a TF circuit essential for AML survival.
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Project description:Transcriptional dysregulation is a prominent feature in leukemia. Here, we systematically surveyed the transcription factor (TF) vulnerabilities in leukemia, and uncovered TF clusters that exhibit context-specific addictions within and between different subtypes of leukemia. We focused on and validated MEF2D as a requirement exclusively in AML with high IRF8 expression. Transcriptomic and chromatin-binding profiling revealed a key TF circuit composed of MEF2D-IRF8 vital for AML maintenance. AML can acquire dependence on this circuit through various mechanisms, including enhancer activation of the circuit via MLL-rearrangement. IRF8 cooperates with PU.1 to control PU.1/MEIS1 co-regulated transcriptional outputs, meanwhile coordinating with MEF2D to directly regulate genes in a non-redundant manner. Collectively, our study nominates a TF circuit in support of the pathogenesis of AML.
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Project description:Cancer cell type-selective addiction of transcription-chromatin regulatory program provides opportunities for therapeutic interventions. Here, we uncovered an IRF8-MEF2D transcription factor (TF) regulatory circuit as an acute myeloid leukemia (AML)-biased dependency. Combining CRISPR-based genetic screens, transcriptional analysis, and chromatin profiling, we demonstrated that a chromatin regulator, ZMYND8, directly regulates IRF8 and MYC expression through occupying AML-specific enhancer regions. ZMYND8 was essential for AML proliferation both in vitro and in vivo. The ZMYND8-occupied IRF8 enhancer was further characterized using Circular Chromosome Conformation Capture and CRISPRi-based perturbation assays and was observed in primary patient cells. Importantly, mutagenesis experiments revealed that the PHD/Bromodomain/PWWP reader module is required for ZMYND8 tethering to leukemia-essential co-activator BRD4 for enhancer-mediated gene regulation. Our results rationalize ZMYND8 as a potential selective therapeutic target for modulating the IRF8/MYC transcriptional networks in AML.
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Project description:This SuperSeries is composed of the SubSeries listed below.
2022-09-07 | GSE186132 | GEO
Project description:Cancer cell type-selective addiction of transcription-chromatin regulatory program provides opportunities for therapeutic interventions. Here, we uncovered an IRF8-MEF2D transcription factor (TF) regulatory circuit as an acute myeloid leukemia (AML)-biased dependency. Combining CRISPR-based genetic screens, transcriptional analysis, and chromatin profiling, we demonstrated that a chromatin regulator, ZMYND8, directly regulates IRF8 and MYC expression through occupying AML-specific enhancer regions. ZMYND8 was essential for AML proliferation both in vitro and in vivo. The ZMYND8-occupied IRF8 enhancer was further characterized using Circular Chromosome Conformation Capture and CRISPRi-based perturbation assays and was observed in primary patient cells. Importantly, mutagenesis experiments revealed that the PHD/Bromodomain/PWWP reader module is required for ZMYND8 tethering to leukemia-essential co-activator BRD4 for enhancer-mediated gene regulation. Our results rationalize ZMYND8 as a potential selective therapeutic target for modulating the IRF8/MYC transcriptional networks in AML.
2021-09-06 | GSE157631 | GEO
Project description:Cancer cell type-selective addiction of transcription-chromatin regulatory program provides opportunities for therapeutic interventions. Here, we uncovered an IRF8-MEF2D transcription factor (TF) regulatory circuit as an acute myeloid leukemia (AML)-biased dependency. Combining CRISPR-based genetic screens, transcriptional analysis, and chromatin profiling, we demonstrated that a chromatin regulator, ZMYND8, directly regulates IRF8 and MYC expression through occupying AML-specific enhancer regions. ZMYND8 was essential for AML proliferation both in vitro and in vivo. The ZMYND8-occupied IRF8 enhancer was further characterized using Circular Chromosome Conformation Capture and CRISPRi-based perturbation assays and was observed in primary patient cells. Importantly, mutagenesis experiments revealed that the PHD/Bromodomain/PWWP reader module is required for ZMYND8 tethering to leukemia-essential co-activator BRD4 for enhancer-mediated gene regulation. Our results rationalize ZMYND8 as a potential selective therapeutic target for modulating the IRF8/MYC transcriptional networks in AML.
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