Modulators of sensitivity to KDM5 inhibition in basal breast cancer (scRNA-seq)
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ABSTRACT:
PROVIDER: PRJNA1095998 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28551345.fastq.gz | Fastqsanger.gz | |||
| SRR28551346.fastq.gz | Fastqsanger.gz | |||
| SRR28551347.fastq.gz | Fastqsanger.gz | |||
| SRR28551348.fastq.gz | Fastqsanger.gz | |||
| SRR28551349.fastq.gz | Fastqsanger.gz |
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Project description:Modulators of sensitivity to KDM5 inhibition in basal breast cancer
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Project description:Modulators of sensitivity to KDM5 inhibition in basal breast cancer (RNA-Seq)
| PRJNA1080531 | ENA
Project description:Modulators of sensitivity to KDM5 inhibition in basal breast cancer (ChIP-Seq)
| PRJNA1080532 | ENA
Project description:We previously identified KDM5B, encoding a histone H3 lysine 4 (H3K4) demethylase, as an oncogene in estrogen receptor positive (ER+) breast cancer driving endocrine resistance. Here we describe that KDM5A is frequently amplified and overexpressed in basal breast tumors and is associated with chemotherapy resistance. Using CRISPR knockout viability screens -/+ KDM5 inhibition (KDM5i), we found that deletion of the transcription factor ZBTB7A and core SAGA complex increased sensitivity to KDM5i, whereas knockout of RHO-GTPases led to resistance. Integrated ChIP-seq and RNA-seq analyses revealed colocalization of ZBTB7A and KDM5s at promoters with high H3K4me3 signal and dependence of KDM5A binding on ZBTB7A. ZBTB7A knockout had a pleiotropic effect on transcriptional responses to KDM5i, in which it modulates the KDM5i-induced innate immune signaling and NF-kB-regulated genes. ZBTB7A knockout and KDM5i cooperate to alter cell states with KDM5i decreasing basal-like and ZBTB7A knockout inducing mesenchymal-like gene expression patterns. Our work furthers our understanding of KDM5-mediated gene regulation in breast cancer and identifies key pathways that mediate sensitivity to KDM5 inhibition
2024-10-14 | GSE259248 | GEO
Project description:We previously identified KDM5B, encoding a histone H3 lysine 4 (H3K4) demethylase, as an oncogene in estrogen receptor positive (ER+) breast cancer driving endocrine resistance. Here we describe that KDM5A is frequently amplified and overexpressed in basal breast tumors and is associated with chemotherapy resistance. Using CRISPR knockout viability screens -/+ KDM5 inhibition (KDM5i), we found that deletion of the transcription factor ZBTB7A and core SAGA complex increased sensitivity to KDM5i, whereas knockout of RHO-GTPases led to resistance. Integrated ChIP-seq and RNA-seq analyses revealed colocalization of ZBTB7A and KDM5s at promoters with high H3K4me3 signal and dependence of KDM5A binding on ZBTB7A. ZBTB7A knockout had a pleiotropic effect on transcriptional responses to KDM5i, in which it modulates the KDM5i-induced innate immune signaling and NF-kB-regulated genes. ZBTB7A knockout and KDM5i cooperate to alter cell states with KDM5i decreasing basal-like and ZBTB7A knockout inducing mesenchymal-like gene expression patterns. Our work furthers our understanding of KDM5-mediated gene regulation in breast cancer and identifies key pathways that mediate sensitivity to KDM5 inhibition
2024-10-14 | GSE259249 | GEO
Project description:We previously identified KDM5B, encoding a histone H3 lysine 4 (H3K4) demethylase, as an oncogene in estrogen receptor positive (ER+) breast cancer driving endocrine resistance. Here we describe that KDM5A is frequently amplified and overexpressed in basal breast tumors and is associated with chemotherapy resistance. Using CRISPR knockout viability screens -/+ KDM5 inhibition (KDM5i), we found that deletion of the transcription factor ZBTB7A and core SAGA complex increased sensitivity to KDM5i, whereas knockout of RHO-GTPases led to resistance. Integrated ChIP-seq and RNA-seq analyses revealed colocalization of ZBTB7A and KDM5s at promoters with high H3K4me3 signal and dependence of KDM5A binding on ZBTB7A. ZBTB7A knockout had a pleiotropic effect on transcriptional responses to KDM5i, in which it modulates the KDM5i-induced innate immune signaling and NF-kB-regulated genes.
2024-10-14 | GSE263161 | GEO
Project description:Alterations in the histone methylation profiles are observed in various types of cancer and targeting of this epigenetic process has therapeutic potential. Here we provide proof-of-principle that pharmacological targeting of KDM5 histone-demethylases is a new strategy for the personalized treatment of HER2-positive breast cancer. This analysis demonstrates that cells characterized by HER2-positivity are particularly sensitive to KDM5 inhibition. The results are confirmed in an appropriate in vivo model with a close structural analogue (KDM5-inh1A). In selected HER2-positive breast cancer cells, we demonstrate synergistic interactions between KDM5-inh1 and HER2-targeting agents (trastuzumab and lapatinib). In addition, HER2-positive cell lines showing innate/acquired resistance to trastuzumab show sensitivity to KDM5-inh1. The levels of KDM5A/B/C proteins, which are selectively targeted by the agent, have no significant association with KDM5-inh1 responsiveness across our panel of breast cancer cell lines, suggesting the existence of other determinants of sensitivity. Using RNA-sequencing data of the breast cancer cell lines, we generate a gene-expression model, consisting of fifteen genes, which is a robust predictor of KDM5-inh1 sensitivity. In a test set of breast cancers, this model correctly predicts sensitivity to the compound in a large fraction of HER2+ tumors. In conclusion, KDM5 inhibition has potential in the treatment of HER2+ breast cancer and our gene-expression model can be developed into a diagnostic tool to select patients who may benefit from treatments based on KDM5-inhibitors.
2019-02-01 | E-MTAB-7433 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below.
2024-10-14 | GSE259252 | GEO
Project description:Mutations in the lysine demethylase 5 (KDM5) family of transcriptional regulators are associated with intellectual disability, yet little is known regarding their spatiotemporal requirements or neurodevelopmental contributions. Utilizing the mushroom body (MB), a major learning and memory center within the Drosophila brain, we demonstrate that KDM5 is required within ganglion mother cells and immature neurons for proper axogenesis. Moreover, the mechanism by which KDM5 functions in this context is independent of its canonical histone demethylase activity. Using in vivo transcriptional and binding analyses, we identify a network of genes directly regulated by KDM5 that are critical modulators of neurodevelopment. We find that KDM5 directly regulates the expression of prospero, a transcription factor that we demonstrate is essential for MB morphogenesis. Prospero functions downstream of KDM5 and binds to approximately half of KDM5-regulated genes. Together, our data provide evidence for a KDM5-Prospero transcriptional axis that is essential for proper MB development.
2021-03-16 | GSE156010 | GEO
Project description:Mutations in the lysine demethylase 5 (KDM5) family of transcriptional regulators are associated with intellectual disability, yet little is known regarding the spatiotemporal requirements or neurodevelopmental contributions of KDM5 proteins. Utilizing the mushroom body (MB), a major learning and memory center within the Drosophila brain, we demonstrate that KDM5 is specifically required within ganglion mother cells and immature neurons for proper neurodevelopment. Within this cellular subpopulation, we identify a core network of KDM5-regulated and -bound genes that are critical modulators of neurodevelopment. Significantly, we find that a majority of these genes are direct targets of Prospero (Pros), a transcription factor with well-established roles in neurodevelopment in other neuronal contexts. We demonstrate that Pros is essential for MB development and show that KDM5 binds to pros and regulates its expression. We therefore provide evidence for a KDM5-Pros axis that orchestrates a transcriptional program critical for proper neurodevelopment.
2021-03-17 | GSE166116 | GEO