The histone demethylase KDM5C functions as a tumor suppressor in AML by repression of bivalently marked immature genes
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA593582 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10588257.fastq.gz | Fastqsanger.gz | |||
| SRR10588258.fastq.gz | Fastqsanger.gz | |||
| SRR10588259.fastq.gz | Fastqsanger.gz | |||
| SRR10588260.fastq.gz | Fastqsanger.gz | |||
| SRR10588261.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 55 |
Similar Datasets
Project description:Epigenetic regulators are frequently mutated in hematological malignancies including acute myeloid leukemia (AML). However, epigenetic dysregulation in AML extends beyond recurrently mutated factors, and only little is known about the potential drivers in this context. Identification and characterization of novel epigenetic drivers affecting AML biology will not only improve our basic understanding of AML, but can also uncover novel options for therapeutic intervention. To uncover novel epigenetic regulators in AML, we performed an in vivo short hairpin RNA (shRNA) screen in the context of Cebpa mutant AML. This led to the identification of the Histone 3 Lysine 4 (H3K4) demethylase, KDM5C, as a novel tumor suppressor in AML. KDM5C potentially functions as a transcriptional repressor via its demethylase activity at promoters, and dysregulation could therefore have widespread consequences. Here, we found that reduced Kdm5c/KDM5C expression is associated with accelerated growth in both human and murine AML cell lines. In vivo, Kdm5c knockdown in a Cebpa mutant AML mouse model resulted in a more aggressive, immature and short-latency phenotype. Mechanistically, we show that knockdown of Kdm5c increased H3K4me3 globally. This translated into the up-regulation of a group of bivalently marked immature genes, resulting in a de-differentiation phenotype which could be reversed by modulating levels of pro-differentiation factors. Finally, we demonstrated that low levels of KDM5C were associated with a decrease in long-term disease-free survival, specifically in female patients. This emphasizes the clinical relevance of our findings and identifies KDM5C as a novel female-biased tumor suppressor in AML.
2023-01-11 | GSE141475 | GEO
Project description:To uncover novel epigenetic regulators in AML, we performed an in vivo short hairpin RNA (shRNA) screen in the context of Cebpa mutant AML. This led to the identification of the Histone 3 Lysine 4 (H3K4) demethylase, KDM5C, as a novel tumor suppressor in AML. KDM5C potentially functions as a transcriptional repressor via its demethylase activity at promoters, and dysregulation could therefore have widespread consequences. Here, we found that reduced Kdm5c/KDM5C expression is associated with accelerated growth in both human and murine AML cell lines. In vivo, Kdm5c knockdown in a Cebpa mutant AML mouse model resulted in a more aggressive, immature and short-latency phenotype. Mechanistically, we show that knockdown of Kdm5c increased H3K4me3 globally. This translated into the up-regulation of a group of bivalently marked immature genes, resulting in a de-differentiation phenotype which could be reversed by modulating levels of pro-differentiation factors. Finally, we demonstrated that low levels of KDM5C were associated with a decrease in long-term disease-free survival, specifically in female patients. This emphasizes the clinical relevance of our findings and identifies KDM5C as a novel female-biased tumor suppressor in AML.
2023-03-10 | PXD016568 | Pride
Project description:Epigenetic regulators are frequently mutated in acute myeloid leukemia (AML). However, epigenetic dysregulation in AML extends beyond recurrently mutated factors and only little is known about the potential drivers in this context. Identification and characterization of novel epigenetic drivers impacting on AML biology will not only improve our basic understanding of AML but may also uncover novel options for therapeutic intervention. To uncover novel epigenetic regulators in AML, we performed an in vivo short hairpin RNA (shRNA) screen in the context of CEBPA mutant AML. We identified the H3K4me2/3 demethylase KDM5C as a novel tumor suppressor in AML. We found that lower Kdm5c/KDM5C expression levels are associated with accelerated growth of human and murine AML cell lines. In a CEBPA mutant AML mouse model, Kdm5c knockdown resulted in a more aggressive, immature and short-latency phenotype. Mechanistically, we show that knockdown of Kdm5c increased H3K4me3-levels globally. This translated into the up-regulation of a group of bivalently marked immature genes resulting in a de-differentiation phenotype which could be reversed by modulating levels of pro-differentiating factors. Finally, we could demonstrate that low levels of KDM5C was associated with a decrease in long-term disease-free survival, specifically in female patients. This emphasizes the clinical relevance of our findings and identifies KDM5C as a novel sex-specific tumor suppressor in AML.
2023-01-11 | GSE141476 | GEO
Project description:Epigenetic regulators are frequently mutated in acute myeloid leukemia (AML). However, epigenetic dysregulation in AML extends beyond recurrently mutated factors and only little is known about the potential drivers in this context. Identification and characterization of novel epigenetic drivers impacting on AML biology will not only improve our basic understanding of AML but may also uncover novel options for therapeutic intervention. To uncover novel epigenetic regulators in AML, we performed an in vivo short hairpin RNA (shRNA) screen in the context of CEBPA mutant AML. We identified the H3K4me2/3 demethylase KDM5C as a novel tumor suppressor in AML. We found that lower Kdm5c/KDM5C expression levels are associated with accelerated growth of human and murine AML cell lines. In a CEBPA mutant AML mouse model, Kdm5c knockdown resulted in a more aggressive, immature and short-latency phenotype. Mechanistically, we show that knockdown of Kdm5c increased H3K4me3-levels globally. This translated into the up-regulation of a group of bivalently marked immature genes resulting in a de-differentiation phenotype which could be reversed by modulating levels of pro-differentiating factors. Finally, we could demonstrate that low levels of KDM5C was associated with a decrease in long-term disease-free survival, specifically in female patients. This emphasizes the clinical relevance of our findings and identifies KDM5C as a novel sex-specific tumor suppressor in AML.
2023-01-11 | GSE153821 | GEO
Project description:The histone demethylase KDM5C functions as a tumor suppressor in AML by repression of bivalently marked immature genes (ChIP-seq)
| PRJNA644289 | ENA
Project description:The histone demethylase KDM5C functions as a tumor suppressor in AML by repression of bivalently marked immature genes (RNA-Seq)
| PRJNA593584 | ENA
Project description:The histone demethylase KDM5C functions as a tumor suppressor in AML by repression of bivalently marked immature genes (ChIP-Seq)
| PRJNA593585 | ENA
Project description:Epigenetic regulators are frequently mutated in hematological malignancies including acute myeloid leukemia (AML). Thus, the identification and characterization of novel epigenetic drivers affecting AML biology holds potential to improve our basic understanding of AML and to uncover novel options for therapeutic intervention. To identify novel tumor suppressive epigenetic regulators in AML, we performed an in vivo short hairpin RNA (shRNA) screen in the context of CEBPA mutant AML. This identified the Histone 3 Lysine 4 (H3K4) demethylase KDM5C as a tumor suppressor, and we show that reduced Kdm5c/KDM5C expression results in accelerated growth both in human and murine AML cell lines, as well as in vivo in Cebpa mutant and inv(16) AML mouse models. Mechanistically, we show that KDM5C act as a transcriptional repressor through its demethylase activity at promoters. Specifically, KDM5C knockdown results in globally increased H3K4me3 levels associated with up-regulation of bivalently marked immature genes. This is accompanied by a de-differentiation phenotype that could be reversed by modulating levels of several direct and indirect downstream mediators. Finally, the association of KDM5C levels with long-term disease-free survival of female AML patients emphasizes the clinical relevance of our findings and identifies KDM5C as a novel female-biased tumor suppressor in AML.
| S-EPMC9991918 | biostudies-literature
Project description:Here, we show that the Kdm5c/Smcx member of the Jarid1 family of H3K4 demethylases is recruited to both enhancer and core promoter elements in ES and neuronal progenitor cells (NPC). Knockdown of Kdm5c deregulates transcription via a local increase in H3K4me3. While at core promoters the function of Kdm5c is to restrict transcription, loss of Kdm5c impairs enhancer function. Remarkably, an impaired enhancer function activates promoter activity from Kdm5c-bound intergenic regions. Our results demonstrate that the Kdm5c demethylase plays a crucial role in the functional identity and discrimination of enhancers and core promoters. We speculate that this is related to recruitment of H3K4me3 binders like the TFIID and NURF complexes6-8. Providing functional identity to genomic regions through balancing enzymes that deposit and remove histone modifications may prove to be a general epigenetic mechanism for the functional indexing of eukaryotic genomes. Examination of the KDM5C binding sites in mouse embryonic stem cells and in neuronal progenitor cells. Effect of KDM5C knock down on H3K4me3 and H3K4me1 levels and gene expression.
2013-04-01 | E-GEOD-34975 | biostudies-arrayexpress
Project description:Here, we show that the Kdm5c/Smcx member of the Jarid1 family of H3K4 demethylases is recruited to both enhancer and core promoter elements in ES and neuronal progenitor cells (NPC). Knockdown of Kdm5c deregulates transcription via a local increase in H3K4me3. While at core promoters the function of Kdm5c is to restrict transcription, loss of Kdm5c impairs enhancer function. Remarkably, an impaired enhancer function activates promoter activity from Kdm5c-bound intergenic regions. Our results demonstrate that the Kdm5c demethylase plays a crucial role in the functional identity and discrimination of enhancers and core promoters. We speculate that this is related to recruitment of H3K4me3 binders like the TFIID and NURF complexes6-8. Providing functional identity to genomic regions through balancing enzymes that deposit and remove histone modifications may prove to be a general epigenetic mechanism for the functional indexing of eukaryotic genomes.
2013-04-01 | GSE34975 | GEO