Interdependence of a mammary-specific super-enhancer and its native promoter facilitates gene activation during pregnancy
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA606279 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11074307.fastq.gz | Fastqsanger.gz | |||
| SRR11074308.fastq.gz | Fastqsanger.gz | |||
| SRR11074309.fastq.gz | Fastqsanger.gz | |||
| SRR11074310.fastq.gz | Fastqsanger.gz | |||
| SRR11074311.fastq.gz | Fastqsanger.gz |
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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.
2020-03-24 | GSE145193 | GEO
Project description:Lineage-specific genetic programs rely on cell-restricted super-enhancers, which are platforms for high-density transcription factor occupation. It is not known whether super-enhancers synergize specifically with their native promoters or provide autonomous and independent regulatory platforms. Here, we investigated 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, alone or in combination with the Wap promoter, to the Tbrg4 gene. While the super-enhancer increased the expression of the Tbrg4 promoter five-fold, the combination of the super-enhancer and promoter resulted in 80-fold gene upregulation, demonstrating lineage-specific promoter-enhancer synergy. Employing ChIP-seq profiling to determine transcription factor binding and identify activating histone marks, we uncovered a chromatin platform that enables the high-level expression of the native promoter-enhancer but not the heterologous promoter. Taken together, our data reveal that lineage-specific enhancer-promoter synergy is critical for mammary gene regulation during pregnancy and lactation.
| S-EPMC7210877 | biostudies-literature
Project description:Lineage-specific genetic programs rely on cell-restricted super-enhancers but it is not clear whether they selectively engage with their associated promoters to attain maximum activity. Exploiting the highly expressed Wap gene, we investigate the relative contributions of the super-enhancer and promoter in mammary tissue during lactation. Employing ChIP-seq profiling and mouse genetics, we uncover a selective lineage-specific promoter-enhancer synergy. Mechanistically, a chromatin platform permissive for high level expression develops in the native promoter-enhancer configuration but not with a heterologous promoter. While this promoter-enhancer synergy permits the induction of gene expression during pregnancy, post-transcriptional mechanisms need to be invoked to account for the high levels of Wap mRNA during lactation. Taken together, our data reveal that lineage-specific enhancer-promoter synergy and post-transcriptional regulation are critical for mammary gene regulation during pregnancy and lactation.
2019-03-01 | GSE121438 | GEO
Project description:Super-enhancers comprise of dense transcription factor platforms highly enriched for active chromatin marks. A paucity of functional data led us to investigate their role in the mammary gland, an organ characterized by exceptional gene regulatory dynamics during pregnancy. ChIP-Seq for the master regulator STAT5, the glucocorticoid receptor, H3K27ac and MED1, identified 440 mammary-specific super-enhancers, half of which were associated with genes activated during pregnancy. We interrogated the Wap super-enhancer, generating mice carrying mutations in STAT5 binding sites within its three constituent enhancers. Individually, only the most distal site displayed significant enhancer activity. However, combinatorial mutations showed that the 1,000-fold gene induction relied on all enhancers. Disabling the binding sites of STAT5, NFIB and ELF5 in the proximal enhancer incapacitated the entire super-enhancer, suggesting an enhancer hierarchy. The identification of mammary-specific super-enhancers and the mechanistic exploration of the Wap locus provide insight into the complexity of cell-specific and hormone-regulated genes. ChIP-Seq for STAT5A, GR, H3K27ac, MED1, NFIB, ELF5, RNA Pol II, and H3K4me3 in wild type (WT) mammary tissues at day one of lactation (L1), and ChIP-Seq for STAT5A, GR, H3K27ac, MED1, NFIB, ELF5, and H3K4me3 in WT mammary tissues at day 13 of pregnancy (p13). ChIP-Seq for STAT5A, GR, H3K27a in Wap-delE1a, -delE1b, -delE1c, -delE2 and -delE3 mutant mammary tissues at L1, and ChIP-Seq for NFIB and ELF5 in Wap-delE1b and -delE1c mutant mammary tissues at L1. ChIP-Seq for H3K4me3 in mammary-epthelial cells at p13 and L1. DNase-seq in WT mammary tissues at L1 and DNase-seq in Wap-delE1a, -delE1c, and -delE3 mutant mammary tissues at L1.
2016-05-31 | E-GEOD-74826 | biostudies-arrayexpress
Project description:Super-enhancers comprise of dense transcription factor platforms highly enriched for active chromatin marks. A paucity of functional data led us to investigate their role in the mammary gland, an organ characterized by exceptional gene regulatory dynamics during pregnancy. ChIP-Seq for the master regulator STAT5, the glucocorticoid receptor, H3K27ac and MED1, identified 440 mammary-specific super-enhancers, half of which were associated with genes activated during pregnancy. We interrogated the Wap super-enhancer, generating mice carrying mutations in STAT5 binding sites within its three constituent enhancers. Individually, only the most distal site displayed significant enhancer activity. However, combinatorial mutations showed that the 1,000-fold gene induction relied on all enhancers. Disabling the binding sites of STAT5, NFIB and ELF5 in the proximal enhancer incapacitated the entire super-enhancer, suggesting an enhancer hierarchy. The identification of mammary-specific super-enhancers and the mechanistic exploration of the Wap locus provide insight into the complexity of cell-specific and hormone-regulated genes.
2016-05-31 | GSE74826 | GEO
Project description:Development of mammary secretory epithelium and its functional differentiation occur during pregnancy under combined actions of ovarian steroids, pituitary hormones and growth factors. If the effect of these molecules is relatively well known, effect of differentiation factors expressed locally is not enough characterized. To understand local regulation of mammary tissue development and differentiation we realized transcriptional analysis on 5 physiological stages (4 during pregnancy and 1 during lactation). An appropriate experimental design was drawn to follow gene expression profiles during differentiation of mammary tissue. Results showed that at mid-pregnancy, mammary tissue was enough defferentiated into secretory epithelium to express milk protein genes and genes of the immune response system actors. But the secretoty activation of mammary epithelium was done only after parturition and wwas characterized by the expression of lipidogenesis genes. Keywords: time course, mammary gland differentiation, goat, pregnancy 18 samples, loop design
2010-05-16 | E-GEOD-14008 | biostudies-arrayexpress
Project description:Development of mammary secretory epithelium and its functional differentiation occur during pregnancy under combined actions of ovarian steroids, pituitary hormones and growth factors. If the effect of these molecules is relatively well known, effect of differentiation factors expressed locally is not enough characterized. To understand local regulation of mammary tissue development and differentiation we realized transcriptional analysis on 5 physiological stages (4 during pregnancy and 1 during lactation). An appropriate experimental design was drawn to follow gene expression profiles during differentiation of mammary tissue. Results showed that at mid-pregnancy, mammary tissue was enough defferentiated into secretory epithelium to express milk protein genes and genes of the immune response system actors. But the secretoty activation of mammary epithelium was done only after parturition and wwas characterized by the expression of lipidogenesis genes. Keywords: time course, mammary gland differentiation, goat, pregnancy
2009-12-23 | GSE14008 | GEO
Project description:The mouse mammary gland undergoes severe morphological changes during each pregnancy cycle. These are controlled by epithelial as well as stromal factors, including fibroblasts. This project aimed to identify factors that are expressed in mammary fibroblasts during early pregnancy (day3) when the first morphological changes become microscopically visible.
2021-09-28 | GSE167438 | GEO
Project description:Pregnancy is the major modulator of mammary gland activity. It induces a tremendous expansion of the mammary epithelium and the generation of alveolar structures for milk production. Anecdotal evidence from multiparous humans indicates that the mammary gland may react less strongly to the first pregnancy than it does to subsequent pregnancies. Here we verify that the mouse mammary gland responds more robustly to a second pregnancy, indicating that the gland retains a long-term memory of pregnancy. A comparison of genome-wide profiles of DNA methylation in isolated mammary cell types revealed substantial and long lasting alterations. The majority of these alterations affect sites occupied by the Stat5a transcription factor and mark specific genes that are upregulated during pregnancy. We postulate that the epigenetic memory of a first pregnancy primes the activation of gene expression networks that promote mammary gland function in subsequent reproductive cycles. More broadly, our data indicate that physiological experience can broadly alter epigenetic states, functionally modifying the capacity of the affected cells to respond to later stimulatory events.
2015-05-15 | GSE67386 | GEO
Project description:Pregnancy is the major modulator of mammary gland activity. It induces a tremendous expansion of the mammary epithelium and the generation of alveolar structures for milk production. Anecdotal evidence from multiparous humans indicates that the mammary gland may react less strongly to the first pregnancy than it does to subsequent pregnancies. Here we verify that the mouse mammary gland responds more robustly to a second pregnancy, indicating that the gland retains a long-term memory of pregnancy. A comparison of genome-wide profiles of DNA methylation in isolated mammary cell types revealed substantial and long lasting alterations. The majority of these alterations affect sites occupied by the Stat5a transcription factor and mark specific genes that are upregulated during pregnancy. We postulate that the epigenetic memory of a first pregnancy primes the activation of gene expression networks that promote mammary gland function in subsequent reproductive cycles. More broadly, our data indicate that physiological experience can broadly alter epigenetic states, functionally modifying the capacity of the affected cells to respond to later stimulatory events. Mammary gland cells (six distinct cell types) from nulliparous and parous female mice were FACS-sorted using a combination of cell surface markers. Genomic DNA was bisulfite converted and used to obtain genome-wide DNA methylation profiles. The current work focuses on the analysis of the first 12 samples (GSM1646785-96) and uses the other two samples to confirm some properties of the analysis results based on samples 1-12. Consequently, samples GSM1646797, GSM1646798 were analyzed in a much more limited manner compared to the other 12 samples, generating two plots included in the associated manucript.
2015-05-15 | E-GEOD-67386 | biostudies-arrayexpress