Condensate-promoting ENL mutation induces tumorigenesis via chromatin remodeling [RNA-seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA999347 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25442616.fastq.gz | Fastqsanger.gz | |||
| SRR25442617.fastq.gz | Fastqsanger.gz | |||
| SRR25442618.fastq.gz | Fastqsanger.gz | |||
| SRR25442619.fastq.gz | Fastqsanger.gz | |||
| SRR25442620.fastq.gz | Fastqsanger.gz |
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Project description:Condensate-promoting ENL mutation induces tumorigenesis via chromatin remodeling
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Project description:Gain-of-function mutations in the chromatin ‘reader’ ENL, identified in AML and Wilms tumor, have been shown to induce aberrant formation of transcriptional condensates in cellular systems. However, the precise role of these mutations and their condensate forming property in tumorigenesis remains unclear. By creating a conditional knock-in mouse model for the most prevalent ENL mutation, we establish ENL mutant as a bona fide oncogenic driver of acute myeloid leukemia in vivo. Heterozygous expression of ENL mutant perturbs the normal hematopoietic hierarchy and results in the aberrant expansion of myeloid progenitors with increased self-renewal property. Furthermore, the ENL mutant remodels histone modifications to alter differentiation processes and drive oncogenic gene expression during hematopoietic development. Importantly, targeted point mutagenesis to disrupt the condensate formation property completely abolishes ENL mutant’s oncogenic function in hematopoietic stem and progenitor cells (HSPCs). Lastly, short-term treatment with a small molecule inhibitor that blocks the acetyl-binding activity of ENL mutant reverts its impact on chromatin and significantly delays leukemia development in mice. Our studies reveal the crucial biological function of mutation-induced transcriptional condensates in chromatin regulation and cancer in vivo and provide proof-of-concept for targeting of pathogenic condensates as a promising therapy for certain cancers.
2024-04-14 | GSE239469 | GEO
Project description:Gain-of-function mutations in the chromatin ‘reader’ ENL, identified in AML and Wilms tumor, have been shown to induce aberrant formation of transcriptional condensates in cellular systems. However, the precise role of these mutations and their condensate forming property in tumorigenesis remains unclear. By creating a conditional knock-in mouse model for the most prevalent ENL mutation, we establish ENL mutant as a bona fide oncogenic driver of acute myeloid leukemia in vivo. Heterozygous expression of ENL mutant perturbs the normal hematopoietic hierarchy and results in the aberrant expansion of myeloid progenitors with increased self-renewal property. Furthermore, the ENL mutant remodels histone modifications to alter differentiation processes and drive oncogenic gene expression during hematopoietic development. Importantly, targeted point mutagenesis to disrupt the condensate formation property completely abolishes ENL mutant’s oncogenic function in hematopoietic stem and progenitor cells (HSPCs). Lastly, short-term treatment with a small molecule inhibitor that blocks the acetyl-binding activity of ENL mutant reverts its impact on chromatin and significantly delays leukemia development in mice. Our studies reveal the crucial biological function of mutation-induced transcriptional condensates in chromatin regulation and cancer in vivo and provide proof-of-concept for targeting of pathogenic condensates as a promising therapy for certain cancers.
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Project description:Condensate-promoting ENL mutation induces tumorigenesis via chromatin remodeling [ChIP-seq and CUT&Tag]
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Project description:This SuperSeries is composed of the SubSeries listed below.
2024-04-14 | GSE239470 | GEO
Project description:Gain-of-function mutations in the histone acetylation 'reader' ENL, found in AML and Wilms tumor, are known to drive condensate formation and gene activation in cellular systems. However, their role in tumorigenesis remains unclear. Using a conditional knock-in mouse model, we show that mutant ENL perturbs normal hematopoiesis, induces aberrant expansion of myeloid progenitors, and triggers rapid onset of aggressive AML. Mutant ENL alters developmental and inflammatory gene programs in part by remodeling histone modifications. Mutant ENL forms condensates in hematopoietic stem/progenitor cells at key leukemogenic genes, and disrupting condensate formation via mutagenesis impairs its chromatin and oncogenic function. Moreover, treatment with an acetyl-binding inhibitor of mutant ENL displaces these condensates from target loci, inhibits mutant ENL-induced chromatin changes, and delays AML initiation and progression in vivo. Our study elucidates the function of ENL mutations in chromatin regulation and tumorigenesis, and demonstrates the potential of targeting pathogenic condensates in cancer treatment.
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Project description:Transcriptional silencing of hypermethylated tumor suppressor genes is a hallmark of tumorigenesis, though the underlying mechanism remains enigmatic. In this study, we find Methyl-CpG-binding domain protein 2 (MBD2) forms nuclear condensate in diverse cancer cells, where it assembles and navigates the chromatin remodeler NuRD complex to these gene loci for transcriptional suppression, thus fueling tumor growth. Disturbance of MBD2 condensate reduces the level of NuRD complex-specific proteins, destabilizes heterochromatin foci, facilitates chromatin relaxation, and consequently impedes tumor progression. We demonstrate that MBD2 condensate is redox sensitive mediated by Cys359. Prooxidative interventions disperse MBD2-NuRD condensate, thereby alleviating the transcriptional repression of tumor suppressor genes. Our findings illuminate a hitherto unappreciated function of MBD2 condensate in sustaining a repressive chromatin state essential for cancer cell proliferation and suggest an oxidative stress targeting approach for malignancies with excessive MBD2 condensate.
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Project description:Transcriptional silencing of hypermethylated tumor suppressor genes is a hallmark of tumorigenesis, though the underlying mechanism remains enigmatic. In this study, we find Methyl-CpG-binding domain protein 2 (MBD2) forms nuclear condensate in diverse cancer cells, where it assembles and navigates the chromatin remodeler NuRD complex to these gene loci for transcriptional suppression, thus fueling tumor growth. Disturbance of MBD2 condensate reduces the level of NuRD complex-specific proteins, destabilizes heterochromatin foci, facilitates chromatin relaxation, and consequently impedes tumor progression. We demonstrate that MBD2 condensate is redox sensitive mediated by Cys359. Prooxidative interventions disperse MBD2-NuRD condensate, thereby alleviating the transcriptional repression of tumor suppressor genes. Our findings illuminate a hitherto unappreciated function of MBD2 condensate in sustaining a repressive chromatin state essential for cancer cell proliferation and suggest an oxidative stress targeting approach for malignancies with excessive MBD2 condensate.
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Project description:Transcriptional silencing of hypermethylated tumor suppressor genes is a hallmark of tumorigenesis, though the underlying mechanism remains enigmatic. In this study, we find Methyl-CpG-binding domain protein 2 (MBD2) forms nuclear condensate in diverse cancer cells, where it assembles and navigates the chromatin remodeler NuRD complex to these gene loci for transcriptional suppression, thus fueling tumor growth. Disturbance of MBD2 condensate reduces the level of NuRD complex-specific proteins, destabilizes heterochromatin foci, facilitates chromatin relaxation, and consequently impedes tumor progression. We demonstrate that MBD2 condensate is redox sensitive mediated by Cys359. Prooxidative interventions disperse MBD2-NuRD condensate, thereby alleviating the transcriptional repression of tumor suppressor genes. Our findings illuminate a hitherto unappreciated function of MBD2 condensate in sustaining a repressive chromatin state essential for cancer cell proliferation and suggest an oxidative stress targeting approach for malignancies with excessive MBD2 condensate.
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Project description:Transcriptional silencing of hypermethylated tumor suppressor genes is a hallmark of tumorigenesis, though the underlying mechanism remains enigmatic. In this study, we find Methyl-CpG-binding domain protein 2 (MBD2) forms nuclear condensate in diverse cancer cells, where it assembles and navigates the chromatin remodeler NuRD complex to these gene loci for transcriptional suppression, thus fueling tumor growth. Disturbance of MBD2 condensate reduces the level of NuRD complex-specific proteins, destabilizes heterochromatin foci, facilitates chromatin relaxation, and consequently impedes tumor progression. We demonstrate that MBD2 condensate is redox sensitive mediated by Cys359. Prooxidative interventions disperse MBD2-NuRD condensate, thereby alleviating the transcriptional repression of tumor suppressor genes. Our findings illuminate a hitherto unappreciated function of MBD2 condensate in sustaining a repressive chromatin state essential for cancer cell proliferation and suggest an oxidative stress targeting approach for malignancies with excessive MBD2 condensate.
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