Expression profiling on lactation day 2 mammary epithelial cells from constitutive miR-150 expressing mice compared to controls.
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE80666 | GEO | 2016/10/01
SECONDARY ACCESSION(S): PRJNA319627
REPOSITORIES: GEO
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Project description:The mammary luminal lineage relies on the common cytokine-sensing transcription factor STAT5 to establish super-enhancers during pregnancy and activate mammary genes required for the nutrition of the offspring. Exploiting progressive differentiation during lactation, we investigated how hormonal cues shape an evolving enhancer landscape and impact the biology of mammary cells. Employing ChIP-seq, we uncover a changing transcription factor occupancy at mammary enhancers. Using mouse genetics, we demonstrate changing biological properties of enhancers as lactation progresses, with individual enhancers gaining strength and an abolished need for the Wap seed enhancer. We further investigated whether permissive chromatin facilitates cell-specific transcription factor binding. Wap enhancers translocated into the widely expressed neighboring Ramp3 gene retained their mammary-specificity and failed to activate the receptive Ramp3 gene in non-mammary tissues. Our studies unveil a previously unrecognized progressive enhancer landscape, in which structurally equivalent components serve unique and differentiation-specific functions. While enhancer redundancy has been suggested and demonstrated for many genes, components of the cytokine-responsive mammary tripartite Wap super-enhancer display a remarkable specificity.
2018-09-18 | GSE115369 | GEO
Project description:The mammary luminal lineage relies on the common cytokine-sensing transcription factor STAT5 to establish super-enhancers during pregnancy and activate mammary genes required for the nutrition of the offspring. Exploiting progressive differentiation during lactation, we investigated how hormonal cues shape an evolving enhancer landscape and impact the biology of mammary cells. Employing ChIP-seq, we uncover a changing transcription factor occupancy at mammary enhancers. Using mouse genetics, we demonstrate changing biological properties of enhancers as lactation progresses, with individual enhancers gaining strength and an abolished need for the Wap seed enhancer. We further investigated whether permissive chromatin facilitates cell-specific transcription factor binding. Wap enhancers translocated into the widely expressed neighboring Ramp3 gene retained their mammary-specificity and failed to activate the receptive Ramp3 gene in non-mammary tissues. Our studies unveil a previously unrecognized progressive enhancer landscape, in which structurally equivalent components serve unique and differentiation-specific functions. While enhancer redundancy has been suggested and demonstrated for many genes, components of the cytokine-responsive mammary tripartite Wap super-enhancer display a remarkable specificity.
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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.
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Project description:Expression profiling on lactation day 2 mammary epithelial cells from constitutive miR-150 expressing mice compared to controls.
| PRJNA319627 | ENA
Project description:We profiled differential gene expression in vivo between pregnant day 14 (secretory differentiation) and lactation day 4 (established secretory activation) using isolated mouse mammary epithelial cells depleted of the mammary adipocytes. Liver-X-Receptors are ligand-dependent transcription factors activated by cholesterol metabolites. These receptors induce a suite of target genes required for de novo synthesis of triglycerides and cholesterol transport in many tissues. Two different isoforms -LXRα and LXRβ- have been well characterized in liver, adipocytes, macrophages and intestinal epithelium among others, but their contribution to cholesterol and fatty acid efflux in the lactating mammary gland is poorly understood. We hypothesize that LXR regulates lipogenesis during milk fat production in lactation. Global mRNA analysis of mouse mammary epithelial cells (MECs) revealed multiple LXR/RXR targets are upregulated sharply at the onset of lactation compared to mid-pregnancy. LXRα is the primary isoform and its protein levels increase throughout lactation in MECs. The LXR agonist GW3965 markedly induced several genes involved in cholesterol transport and lipogenesis and enhanced cytoplasmic lipid droplet accumulation in the HC11 MEC cell line. Importantly, in vivo pharmacological activation of LXR increased the milk cholesterol percentage and induced Srebp1c and Abca7 expression in MECs. Cumulatively, our findings identify LXRα as an important regulator of cholesterol incorporation into the milk through key nodes of de novo lipogenesis, suggesting a potential therapeutic target in women with difficulty initiating lactation.
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Project description:Lineage-specific genetic programs rely on cell-restricted super-enhancers, platforms for high-density occupation by transcription factors. It is not known whether super-enhancers synergize specifically with their native promoters or provide autonomous regulatory platforms. Here we investigate the ability of the mammary Wap super-enhancer to activate the promoter of the juxtaposed and ubiquitously expressed Tbrg4 gene in the mouse mammary gland. The Wap super-enhancer was fused, by itself or in combination with its promoter, with the Tbrg4 gene. While the Wap super-enhancer activated the Tbrg4 promoter five-fold, the combination of Wap super-enhancer and promoter resulted in an 80-fold gene activation, demonstrating lineage-specific promoter-enhancer synergy. Employing ChIP-seq profiling, we uncover a chromatin platform permissive for high level expression that develops in the native promoter-enhancer context but not with a heterologous promoter. Post-transcriptional mechanisms through the Wap 3’UTR have been proposed to account for the exceptional high mRNA levels during lactation, but our mouse genetic experiments failed to support this. Lastly, we discovered that the CREB transcription factor is an integral part of the Tbrg4 promoter but not essential for its function. Taken together, our data reveal that lineage-specific enhancer-promoter synergy is critical for mammary gene regulation during pregnancy and lactation.
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