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Loss of EZH2 results in enhanced recruitment of EZH1, Pol II and Stat5 and precocious mammary gland development

ABSTRACT: 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

ORGANISM(S): Mus musculus

SUBMITTER: Keunsoo Kang

PROVIDER: E-GEOD-65284 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Loss of EZH2 results in precocious mammary gland development and the activation of STAT5-dependent genes

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

EZH2 controls mammary differentiation independently of its methyltransferase activity through controlling genomic STAT5 access

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

Loss of EZH2 results in precocious mammary gland development and the activation of STAT5-dependent genes

2015-08-31 | GSE70440 | GEO

Loss of EZH2 results in enhanced recruitment of EZH1, Pol II and Stat5 and precocious mammary gland development

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.

2015-01-27 | GSE65284 | GEO

EZH2 controls mammary differentiation independently of its methyltransferase activity through controlling genomic STAT5 access

2013-12-31 | GSE52016 | GEO

Disruption of H3K27me3 through loss of EZH1 and EZH2 accelerates progression of hepatosteatosis to fatal liver fibrosis

Project description:Although epigenetic mechanisms, such as specific histone modifications, control common and cell-specific genetic programs, a role for histone modifying enzymes in liver metabolism and disease has not been investigated. This report demonstrates that the combined loss of the histone methyltransferases EZH1 and EZH2 in mouse hepatocytes led to the disruption of H3K27me3 homeostasis by age three months, simple fatty liver by age six months and fatal fibrosis by age 15 months. Global and gene-specific reduction of H3K27me3 marks paralleled a concomitant increase of H3K4me3 marks at genes associated with chronic liver disease. Advanced disease was accompanied by widespread infiltration of immune cells, an increase of activated hepatic stellate cells and collagen deposition. Expression of genes from the cytochrome P450 family that control drug metabolism was already deregulated by age two months and mice were fatally hypersensitive to carbon tetrachloride (CCl4). These genetic experiments, for the first time, illustrate that the simple loss of EZH1/EZH2, which results in the disruption of epigenetic modifications, is sufficient for the progression of fatal liver disease. RNA-seq and ChIP-seq were performed in liver tissues.

2013-12-24 | E-GEOD-53627 | biostudies-arrayexpress

Pregnancy-induced gene expression and differentiation of mouse mammary epithelium are co-governed by Nuclear Factor IB (NFIB) and STAT5

Project description:Cytokines control the expression of common and cell-specific genes through the transcription factor STAT5. In mammary tissue specifically, expression of approximately 570 genes is induced during pregnancy by prolactin through STAT5, which binds to putative regulatory sequences. We have now asked whether mammary-specific induction of these genes can be linked to the presence of additional transcription factors, which would act in concert with STAT5. RNA-seq analysis at parturition identified 370 genes that were under NFIB control. Notably, 75% of these genes, encoding proteins linked to the differentiation of mammary epithelium, were also regulated by STAT5. This study demonstrates that the STAT5-NFIB module is an essential part of genes that define differentiation and function of the mammary gland. Expression profiling by high throughput sequencing in wild-type (WT) and Nfib-null (KO) mammary gland tissues

2012-12-13 | E-GEOD-42878 | biostudies-arrayexpress

Pregnancy-induced gene expression and differentiation of mouse mammary epithelium are co-governed by Nuclear Factor IB (NFIB) and STAT5

2012-12-13 | GSE42878 | GEO

Expression data from LSK cells from mice with knock-out of Ezh1 versus LSK control

Project description:Ezh1 is a protein member of PRC2. Ezh1 has been described as a functional repressor gene, such as its homologous Ezh2. We are investigating the role of Ezh1 in hematopoietic stem cells, aging, self-renewal and differentiation. We used microarrays to detail the global program of gene expression in LSK cells from mice with knocked-down expression of Ezh1. LSK cells from EZH1 knockout and control mice were marked and isolated by fluorescence-activated cell sorting. 2 replicates each.

2012-03-06 | E-GEOD-36288 | biostudies-arrayexpress

Polycomb Protein Ezh1 Promotes RNA Polymerase II Elongation

Project description:Polycomb group (PcG) proteins initiate the formation of repressed chromatin domains and regulate developmental gene expression. A mammalian PcG protein, Enhancer of Zeste homolog 2 (Ezh2), triggers transcriptional repression by catalyzing the addition of methyl groups onto lysine-27 of histone H3 (H3K27me2/3)1. This action facilitates the binding of other PcG proteins to histone H3 and compaction of chromatin. Interestingly, there exists a paralog of Ezh2, termed Ezh1, whose primary function remains unclear. Here, we provide evidence for genome-wide association of Ezh1 with active epigenetic marks, RNA polymerase II (PolII) and mRNA production. Ezh1 depletion reduced global PolII occupancy within gene bodies and resulted in delayed transcriptional activation during differentiation of skeletal muscle cells. Conversely, ectopic expression of wild-type Ezh1 led to premature gene activation and rescued PolII-elongation defects in Ezh1-depleted cells. Collectively, these findings reveal an unanticipated role of a PcG protein in promoting mRNA transcription. Examination of 3 different histone modifications, 3 modified forms of RNA polymerase II, Ezh1, Ezh2 and mRNA levels in a skeletal muscle cells at various developmental stages.

2011-11-23 | E-GEOD-25549 | biostudies-arrayexpress

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