Repression of Igf1 expression by Ezh2 prevents basal cell differentiation in the developing lung
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE57393 | GEO | 2015/05/11
SECONDARY ACCESSION(S): PRJNA246378
REPOSITORIES: GEO
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Project description:Gene expression (RNA-seq) and H3K27me3 binding (ChIP-seq) profiling of wild type and Ezh2-deficient mouse lung epithelium. Lungs from wild type and Ezh2-deficient mice (Ezh2 deletion is specific to lung epithelium) were collected at day e16.5. Lung cells were separated into epithelial and stromal populations based on EpCAM expression. Epithelial cells were profiled for both gene expression (Total RNA-seq) and H3K27me3 binding (ChIP-seq). Additionally, stromal cells were also profiled for gene expression.
2015-05-11 | E-GEOD-57393 | biostudies-arrayexpress
Project description:Epigenetic mechanisms involved in the establishment of lung epithelial cell lineage identities during development are largely unknown. Here, we explored the role of the histone methyltransferase Ezh2 during lung lineage determination. Loss of Ezh2 in the lung epithelium leads to defective lung formation and perinatal mortality. We show that Ezh2 is crucial for airway lineage specification and alveolarization. Using optical projection tomography imaging, we found that branching morphogenesis is affected in Ezh2 conditional knockout mice and the remaining bronchioles are abnormal, lacking terminally differentiated secretory club cells. Remarkably, RNA-seq analysis revealed the upregulation of basal genes in Ezh2-deficient epithelium. Three-dimensional imaging for keratin 5 further showed the unexpected presence of a layer of basal cells from the proximal airways to the distal bronchioles in E16.5 embryos. ChIP-seq analysis indicated the presence of Ezh2-mediated repressive marks on the genomic loci of some but not all basal genes, suggesting an indirect mechanism of action of Ezh2. We found that loss of Ezh2 de-represses insulin-like growth factor 1 (Igf1) expression and that modulation of IGF1 signaling ex vivo in wild-type lungs could induce basal cell differentiation. Altogether, our work reveals an unexpected role for Ezh2 in controlling basal cell fate determination in the embryonic lung endoderm, mediated in part by repression of Igf1 expression.
| S-EPMC4392602 | biostudies-literature
Project description:Overexpression of EZH2 in estrogen receptor negative (ER-) breast cancer promotes metastasis. EZH2 has been mainly studied as the catalytic component of the Polycomb Repressive Complex 2 (PRC2) that mediates gene repression by trimethylating histone H3 at lysine 27 (H3K27me3). However, how EZH2 drives metastasis despite the low H3K27me3 levels observed in ER- breast cancer is unknown. We have shown that in human invasive carcinomas and distant metastases, cytoplasmic EZH2 phosphorylated at T367 is significantly associated with ER- disease and low H3K27me3 levels. Here, we explore the interactome of EZH2 and of a phosphodeficient mutant EZH2_T367A. We identified novel interactors of EZH2, and identified interactions that are dependent on the phosphorylation and cellular localization of EZH2 that may play a role in EZH2 dependent metastatic progression.
2018-07-03 | PXD010073 | Pride
Project description:Repression of Igf1 expression by Ezh2 prevents basal cell differentiation in the developing lung
| PRJNA246378 | ENA
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: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: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: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:This SuperSeries is composed of the following subset Series: GSE40970: ChIP-seq analysis of H3K27me3 histone modification in EZH2 mutant and wild type DLBCL cell lines GSE40971: Gene expression profiling of EZH2 mutant and wild type DLBCL cell lines treated with EZH2 inhibitor GSE41239: Gene expression profiling of two DLBCL cell lines upon shRNA mediated knockdown of EZH2 Refer to individual Series
2012-10-12 | E-GEOD-40972 | biostudies-arrayexpress
Project description:We hypothesized that EZH2 could be involved in immune escape in Merkel Cell Carcinoma (MCC). In this context, we aimed at evaluating whether EZH2 might contribute to HLA-I expression repression in MCC. To this purpose, we first investigated whether low/lack of HLA-I expression is associated with high H3K27me3 levels in MCC tumor samples. Whole proteome analysis of the PeTa cell line by mass spectrometry after DZNeP treatment (EZH2 inhibitor) revealed upregulation of proteins involved in Fc receptor, as well as antigen processing and presentation pathways components.
2023-11-21 | PXD040973 | Pride