Chemical reprogramming of human fibroblasts
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE123668 | GEO | 2018/12/12
REPOSITORIES: GEO
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Project description:We previously described that the KDM5B histone H3 lysine 4 (H3K4) demethylase is an oncogene in estrogen receptor-positive breast cancer. Here we report that KDM5A is 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 ZBTB7A transcription factor and core SAGA complex sensitized to KDM5i, whereas knockout of RHO-GTPases led to resistance. ChIP-seq and RNA-seq analyses revealed colocalization of ZBTB7A and KDM5A/B at promoters with high H3K4me3 and dependence of KDM5A binding on ZBTB7A. ZBTB7A knockout altered transcriptional response to KDM5i specifically at NF-kB target genes, oxidative phosphorylation, and E2F-driven proliferation pathways. Our work furthers understanding of KDM5-mediated gene regulation in breast cancer and identified key pathways mediating sensitivity to KDM5i.
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Project description:Tri-methylation on histone H3 lysine 4 (H3K4me3) is enriched near transcription start sites and correlates with active transcription. Like other histone marks, methylation on H3K4 is catalyzed by the respective methyltransferases and erased by demethylases. Lysine demethylase 5 (KDM5) family of Fe (II) and α-ketoglutarate-dependent dioxygenases removes the methyl groups from H3K4me3. All four family members of KDM5 demethylases (KDM5A-D) share sequence identity, have similar in vitro kinetic parameters, and display functional redundancy. To determine the effects of complete depletion of KDM5 activity, we treated MCF7 cells with DMSO, or two pan-KDM5 specific inhibitors, KDM5-C70 (our lab code 443) and CPI-48 (our lab code 278) and performed RNA sequencing to determine gene expression changes after KDM5 inhibitor treatment.
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Project description:We perfomed ChIP-seq using KDM5A antibodies in T47D cells after 24 hour treatment with the AKT inhibitor MK2206 or DMSO. We show that the cistrome of the H3K4 demethylase KDM5A is affected by AKT inhibition. Comparison of genome-wide KDM5A binding after AKT inhibition vs vehicle
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Project description:Histone H3K4 methylation has been linked to transcriptional activation. JARID1A (also known as RBP2 or KDM5A), a member of the JARID1 protein family, is an H3K4 demethylase, previously implicated in the regulation of transcription and differentiation. Here we show that JARID1A is physically and functionally associated with two histone deacetylase complexes. Immunoaffinity purification of JARID1A confirmed a previously described association with the SIN3B-containing HDAC complex, and revealed an association with the nucleosome remodeling and deacetylase (NuRD) complex. Sucrose density gradient and sequential immunoprecipitation analyses further confirmed the stable association of JARID1A with these two HDAC complexes. JARID1A depletion led to changes in the expression of hundreds of genes, two-thirds of which were also controlled by CHD4, the NuRD catalytic subunit. Gene ontology analysis confirmed that the genes commonly regulated by both JARID1A and CHD4 were categorized as developmentally regulated genes. ChIP analyses suggested that CHD4 controls chromatin association with JARID1A and modulates H3K4 levels at the promoter and coding regions of target genes. We further demonstrated that the C. elegans homologues of JARID1 and CHD4 function in the same pathway during vulva development. Taken together, these results suggest that JARID1A and the NuRD complex cooperatively function to control developmentally regulated genes. Genome-wide transcriptomic analysis of HeLa cells transfected with JARID1A complex component siRNA
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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
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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 perfomed ChIP-seq using KDM5A antibodies in T47D cells after 24 hour treatment with the AKT inhibitor MK2206 or DMSO. We show that the cistrome of the H3K4 demethylase KDM5A is affected by AKT inhibition.
2016-06-14 | GSE80593 | GEO
Project description:Histone H3K4 methylation has been linked to transcriptional activation. JARID1A (also known as RBP2 or KDM5A), a member of the JARID1 protein family, is an H3K4 demethylase, previously implicated in the regulation of transcription and differentiation. Here we show that JARID1A is physically and functionally associated with two histone deacetylase complexes. Immunoaffinity purification of JARID1A confirmed a previously described association with the SIN3B-containing HDAC complex, and revealed an association with the nucleosome remodeling and deacetylase (NuRD) complex. Sucrose density gradient and sequential immunoprecipitation analyses further confirmed the stable association of JARID1A with these two HDAC complexes. JARID1A depletion led to changes in the expression of hundreds of genes, two-thirds of which were also controlled by CHD4, the NuRD catalytic subunit. Gene ontology analysis confirmed that the genes commonly regulated by both JARID1A and CHD4 were categorized as developmentally regulated genes. ChIP analyses suggested that CHD4 controls chromatin association with JARID1A and modulates H3K4 levels at the promoter and coding regions of target genes. We further demonstrated that the C. elegans homologues of JARID1 and CHD4 function in the same pathway during vulva development. Taken together, these results suggest that JARID1A and the NuRD complex cooperatively function to control developmentally regulated genes.
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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.
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Project description:Histone modifications are critical for regulating chromatin structure and gene expression. Dysregulation of histone modifications likely contributes to disease states and cancer. Depletion of the chromatin-binding protein BRWD3, a known substrate-specificity factor of the Cul4-DDB1 E3 ubiquitin ligase complex, results in increased in H3K4me1 levels. The underlying mechanism linking BRWD3 and H3K4 methylation, however, has yet to be defined. Here, we show that depleting BRWD3 not only causes an increase in H3K4me1 levels, but also causes a decrease in H3K4me3 levels, indicating that BRWD3 influences H3K4 methylation more broadly. Using immunoprecipitation coupled to quantitative mass spectrometry, we identified an interaction between BRWD3 and the H3K4-specific demethylase 5 (KDM5/Lid), an enzyme that removes tri- and di- methyl marks from H3K4. Moreover, analysis of ChIP-seq data revealed that BRWD3 and KDM5 are significantly co-localized throughout the genome and that sites of H3K4me3 are highly enriched at BRWD3 binding sites. We show that BRWD3 promotes K48-linked polyubiquitination and degradation of KDM5 and that KDM5 degradation is dependent on both BRWD3 and Cul4. Critically, depleting KDM5 fully restores altered H3K4me3 levels and partially restores H3K4me1 levels upon BRWD3 depletion. Together, our results demonstrate that BRWD3 regulates KDM5 activity to balance H3K4 methylation levels.
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