Ezh2 promotes mammary tumor initiation through the epigenetic regulation of the Wnt and mTORC1 signaling pathways (RNA-Seq)
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ABSTRACT:
PROVIDER: PRJNA984668 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24951501_1.fastq.gz | Fastqsanger.gz | |||
| SRR24951501_2.fastq.gz | Fastqsanger.gz | |||
| SRR24951502_1.fastq.gz | Fastqsanger.gz | |||
| SRR24951502_2.fastq.gz | Fastqsanger.gz | |||
| SRR24951503_1.fastq.gz | Fastqsanger.gz |
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Project description:The regulation of gene expression through histone post-translational modifications plays a crucial role in breast cancer progression. However, the molecular mechanisms underlying the contribution of histone modification to tumor initiation remain unclear. To gain a deeper understanding of the role of the histone modifier Enhancer of Zeste homology 2 (Ezh2) in the early stages of mammary tumor progression, we employed an inducible mammary organoid system bearing conditional Ezh2 alleles that faithfully recapitulates key events of Luminal B breast cancer initiation. We showed that the loss of Ezh2 severely impairs oncogene-induced organoid growth, with Ezh2-deficient organoids maintaining a polarized epithelial phenotype. Transcriptomic profiling showed that Ezh2-deficient mammary epithelial cells upregulated the expression of negative regulators of Wnt signaling and downregulated genes involved in mTORC1 (mechanistic target of rapamycin complex 1) signaling. We identified Sfrp1, a Wnt signaling suppressor, as an Ezh2 target gene that is de-repressed and expressed in Ezh2-deficient epithelium. Furthermore, an analysis of breast cancer data revealed that Sfrp1 expression was associated with favorable clinical outcomes in Luminal B breast cancer patients. Finally, we confirmed that targeting Ezh2 impairs mTORC1 activity through an indirect mechanism that upregulates the expression of the tumour suppressor Pten. These findings indicate that Ezh2 integrates the mTORC1 and Wnt signaling pathways during early mammary tumor progression, arguing that inhibiting Ezh2 or therapeutically targeting Ezh2-dependent programs could be beneficial for the treatment of early-stage Luminal B breast cancer.
2023-07-15 | GSE235144 | GEO
Project description:The regulation of gene expression through histone post-translational modifications plays a crucial role in breast cancer progression. However, the molecular mechanisms underlying the contribution of histone modification to tumor initiation remain unclear. To gain a deeper understanding of the role of the histone modifier Enhancer of Zeste homology 2 (Ezh2) in the early stages of mammary tumor progression, we employed an inducible mammary organoid system bearing conditional Ezh2 alleles that faithfully recapitulates key events of Luminal B breast cancer initiation. We showed that the loss of Ezh2 severely impairs oncogene-induced organoid growth, with Ezh2-deficient organoids maintaining a polarized epithelial phenotype. Transcriptomic profiling showed that Ezh2-deficient mammary epithelial cells upregulated the expression of negative regulators of Wnt signaling and downregulated genes involved in mTORC1 (mechanistic target of rapamycin complex 1) signaling. We identified Sfrp1, a Wnt signaling suppressor, as an Ezh2 target gene that is de-repressed and expressed in Ezh2-deficient epithelium. Furthermore, an analysis of breast cancer data revealed that Sfrp1 expression was associated with favorable clinical outcomes in Luminal B breast cancer patients. Finally, we confirmed that targeting Ezh2 impairs mTORC1 activity through an indirect mechanism that upregulates the expression of the tumour suppressor Pten. These findings indicate that Ezh2 integrates the mTORC1 and Wnt signaling pathways during early mammary tumor progression, arguing that inhibiting Ezh2 or therapeutically targeting Ezh2-dependent programs could be beneficial for the treatment of early-stage Luminal B breast cancer.
2023-07-15 | GSE235145 | GEO
Project description:Ezh2 promotes mammary tumor initiation through the epigenetic regulation of the Wnt and mTORC1 signaling pathways
| PRJNA984661 | ENA
Project description:Ezh2 promotes mammary tumor initiation through epigenetic regulation of the Wnt and mTORC1 signaling pathways (ChIP-Seq)
| PRJNA984669 | ENA
Project description:This SuperSeries is composed of the following subset Series: GSE25331: Initiation pausing of mRNA translation controlled by mTORC1 signaling (microarray) GSE25626: Initiation pausing of mRNA translation controlled by mTORC1 signaling (RNA-Seq) Refer to individual Series
2011-11-12 | E-GEOD-25627 | biostudies-arrayexpress
Project description:Establishment and differentiation of mammary alveoli during pregnancy are controlled by prolactin through the transcription factor STAT5. As pregnancy progresses mammary signature genes are activated in a defined temporal order, which coincides with the recruitment of STAT5 to respective regulatory sequences. This study addressed the question whether the methyltransferase and transcriptional co-activator EZH2 controls the differentiation clock of mammary epithelium. Ablation of Ezh2 from mammary stem cells resulted in precocious differentiation of alveolar epithelium during pregnancy and the activation of mammary-specific STAT5 target genes. This coincided with enhanced occupancy by STAT5, EZH1 and Pol II to these loci. Limited activation of differentiation-specific genes was also observed in mammary epithelium lacking both EZH2 and STAT5, suggesting a modulating but not mandatory role for STAT5. Notably, loss of EZH2 did not result in overt changes in genome-wide and gene-specific H3K27me3 patterns, suggesting that enhanced EZH1 recruitment can compensate for the loss of EZH2. Differentiated mammary epithelia failed to form in the combined absence of EZH1 and EZH2. Transplantation experiments failed to demonstrate a role for EZH2 in the biology of mammary stem and progenitor cells. In summary, while EZH1 and EZH2 serve redundant functions in the establishment of H3K27me3 and formation of mammary alveoli, the presence of EZH2 is required to obtain controlled temporal differentiation of mammary epithelium. mRNA-seq in WT;MMTV-Cre (Control) at p13 and p18, E1-/- (E1KO), Ezh2f/f;MMTV-Cre(E2KO), Stat5f/f;MMTV-Cre(S5KO), and Ezh2f/f;Stat5f/f;MMTV-Cre (E2S5DKO) at p13 mammary tissues. ChIP-seq for H3K27me3, STAT5, EZH1, EZH2 and PolII in mammary tissues at p13
2015-08-31 | E-GEOD-70440 | biostudies-arrayexpress
Project description:Mammary development is characterized by the proliferation and progressive differentiation of alveolar epithelium during pregnancy, culminating in lactation. These processes are largely controlled by hormones through transcription factors. We now explore the contributions of histone methyltransferases, which establish H3K27me3 marks, in the temporally-regulated differentiation of mammary epithelium. Loss of EZH2, but not EZH1, resulted in precocious mammary differentiation, which was facilitated by STAT5 binding to specific target genes and their activation. Mammary stem cells were not compromised in the absence of EZH2. Genome-wide H3K27me3 patterns remained intact in the absence of EZH2. Mammary-specific loci were devoid of H3K27me3 marks in mammary progenitor and mature cells, suggesting no regulatory role for this repressive mark. Lastly, the combined absence of EZH1 and EZH2 inhibited the formation of alveoli. Taken together, EZH2 controls temporally-restricted differentiation of mammary epithelium through H3K27me3-independent mechanisms. mRNA-seq and ChIP-seq in MMTV-Cre (Control), E1-/- (E1KO), E1+/-;E2f/f;control (E1+/-E2KO) and Ezh2f/f;control (E2KO) mammary gland tissues or MECs (purified mammary epithelial cells). H3K27me3 and STAT5 ChIP-seqs in mammary tissues at p13; H3K4me3 ChIP-seq in MECs (mammary epithelial cells) at p13; RNA-seqs at mature virgin (with/without prolactin injection), p13 and p18 mammary tissues.
2013-12-31 | E-GEOD-52016 | biostudies-arrayexpress
Project description:Mammary development is characterized by the proliferation and progressive differentiation of alveolar epithelium during pregnancy, culminating in lactation. These processes are largely controlled by hormones through transcription factors. We now explore the contributions of histone methyltransferases, which establish H3K27me3 marks, in the temporally-regulated differentiation of mammary epithelium. Loss of EZH2, but not EZH1, resulted in precocious mammary differentiation, which was facilitated by STAT5 binding to specific target genes and their activation. Mammary stem cells were not compromised in the absence of EZH2. Genome-wide H3K27me3 patterns remained intact in the absence of EZH2. Mammary-specific loci were devoid of H3K27me3 marks in mammary progenitor and mature cells, suggesting no regulatory role for this repressive mark. Lastly, the combined absence of EZH1 and EZH2 inhibited the formation of alveoli. Taken together, EZH2 controls temporally-restricted differentiation of mammary epithelium through H3K27me3-independent mechanisms.
2013-12-31 | GSE52016 | GEO
Project description:Establishment and differentiation of mammary alveoli during pregnancy are controlled by prolactin through the transcription factor STAT5. As pregnancy progresses mammary signature genes are activated in a defined temporal order, which coincides with the recruitment of STAT5 to respective regulatory sequences. This study addressed the question whether the methyltransferase and transcriptional co-activator EZH2 controls the differentiation clock of mammary epithelium. Ablation of Ezh2 from mammary stem cells resulted in precocious differentiation of alveolar epithelium and accelerated activation of mammary signature genes. This coincided with enhanced occupancy by EZH1, Pol II and STAT5 to mammary-specific loci. Notably, loss of EZH2 did not result in overt changes in genome-wide and gene-specific H3K27me3 patterns, suggesting that enhanced EZH1 recruitment can compensate for the loss of EZH2. However, differentiated mammary epithelia failed to form in the combined absence of EZH1 and EZH2. Transplantation experiments failed to demonstrate a role for EZH2 in the biology of mammary stem and progenitor cells. In summary, while EZH1 and EZH2 serve redundant functions in the establishment of H3K27me3 and formation of mammary alveoli, the presence of EZH2 is required to obtain controlled temporal differentiation of mammary epithelium. ChIP-seq EZH1, EZH2, PolIII; WT and E2KO mammary cells
2015-01-27 | E-GEOD-65284 | biostudies-arrayexpress
Project description:Metaplastic breast carcinomas (mBrCAs) are a highly aggressive subtype of triple negative breast cancer (TNBC) with histological evidence of epithelial to mesenchymal transition (EMT) and aberrant differentiation, including varied non-glandular features. CCN6/WISP3 tumor suppressor gene inactivation and b-catenin-dependent Wnt pathway activation are often seen in mBrCAs. We have reported MMTV-Cre;Ccn6fl/fl (Ccn6-KO) mice develop spindle mBrCAs with EMT and elevated expression of the Wnt/b-catenin pathway genes HMGA2 and IGF2BP2. The mechanisms by which the secreted CCN6 protein exerts tumor suppressor functions in breast tissues are uncertain. Here, we show recombinant CCN6 protein interacts with Wnt receptor FZD8 and co-receptor LRP6 on mBrCA cells to antagonize Wnt ligand-mediated activation of b-catenin/T-cell-factor (TCF) transcription. We identify the gene for histone methyltransferase EZH2, the catalytic component of polycomb repressive complex 2, as a β-catenin/TCF transcriptional target in Ccn6-KO mBrCA cells. Inhibition of Wnt/β-catenin/TCF function in Ccn6-KO mBrCA cells led to reduced EZH2 levels and decreased histone H3 lysine 27 trimethylation, resulting in deregulation of specific gene targets. Pharmacological inhibition of EZH2 reduced growth and metastasis of Ccn6-KO mBrCA mammary tumors and induced an epithelial phenotype in vivo. In human breast cancer specimens, low CCN6 is significantly associated with activated β-catenin and high EZH2 in spindle mBrCAs compared to other subtypes. Collectively, our findings establish a novel tumor suppressor mechanism for CCN6 as a key negative regulator of a b-catenin/TCF-EZH2 axis and highlight how CCN6 restoration or b-catenin or EZH2 inhibition could have therapeutic relevance for patients with spindle mBrCAs.
2024-07-10 | GSE250574 | GEO