Progressing enhancer landscape during mammary differentiation controls gene regulation [ChIP-seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA474724 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7265450.fastq.gz | Fastqsanger.gz | |||
| SRR7265460.fastq.gz | Fastqsanger.gz | |||
| SRR7265470.fastq.gz | Fastqsanger.gz | |||
| SRR7265480.fastq.gz | Fastqsanger.gz | |||
| SRR7265490.fastq.gz | Fastqsanger.gz |
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Project description:Progressing enhancer landscape during mammary differentiation controls gene regulation [RNA-seq]
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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.
2018-09-18 | GSE115368 | GEO
Project description:The mammary luminal lineage relies on the common cytokine-sensing transcription factor STAT5 to establish super-enhancers during pregnancy and initiate a genetic program that activates milk production. As pups grow, the greatly increasing demand for milk requires progressive differentiation of mammary cells with advancing lactation. Here we investigate how persistent hormonal exposure during lactation shapes an evolving enhancer landscape and impacts the biology of mammary cells. Employing ChIP-seq, we uncover a changing transcription factor occupancy at mammary enhancers, suggesting that their activities evolve with advancing differentiation. Using mouse genetics, we demonstrate that the functions of individual enhancers within the Wap super-enhancer evolve as lactation progresses. Most profoundly, a seed enhancer, which is mandatory for the activation of the Wap super-enhancer during pregnancy, is not required during lactation, suggesting compensatory flexibility. Combinatorial deletions of structurally equivalent constituent enhancers demonstrated differentiation-specific compensatory activities during lactation. We also demonstrate that the Wap super-enhancer, which is built on STAT5 and other common transcription factors, retains its exquisite mammary specificity when placed into globally permissive chromatin, suggesting a limited role of chromatin in controlling cell specificity. Our studies unveil a previously unrecognized progressive enhancer landscape where structurally equivalent components serve unique and differentiation-specific functions.
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Project description:Signal Transducers and Activators of Transcription (STATs) are principal transcription factors downstream of cytokine receptors. Although STAT5A is expressed in most tissues it remains to be understood why its premier, non-redundant functions are restricted to prolactin-induced mammary gland development. We report that the ubiquitously expressed Stat5a/b locus is subject to lineage-specific transcriptional control in mammary epithelium. Genome-wide surveys of epigenetic status and transcription factor occupancy uncovered a putative mammary-specific enhancer within the intergenic sequences separating the two Stat5 genes. This region exhibited several hallmarks of genomic enhancers, including DNaseI hypersensitive sites, H3K27 acetylation and binding by GR and MED1. Mammary-specific STAT5 binding was obtained at two canonical STAT5 binding motifs. CRISPR/Cas9-mediated genome editing was used to delete these STAT5 binding sites in mice and determine their biological function. Mutant animals exhibited an 80% reduction of Stat5 levels in mammary epithelium and a concomitant reduction of STAT5-dependent gene expression. Transcriptome analysis identified a class of mammary-restricted genes that was particularly dependent on high STAT5 levels as a result of the intergenic enhancer. Taken together, the mammary-specific enhancer enables a positive feedback circuit that underlies the remarkable abundance of STAT5 and, in turn, controls the efficacy of STAT5-dependent mammary physiology. ChIP-seq for H3K27ac, RNA Pol II, and MED1 in mammary tissues at L1, and ChIP-seq for H3K27ac and GR in mammary tissues at p13. mRNA-seq in WT at L1, line B (GAS2 mutation only) and line C (both GAS1 and GAS2 mutations) at L1 in mammary tissues, and DNase-seq in WT mammary tissues at L1.
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Project description:Signal Transducers and Activators of Transcription (STATs) are principal transcription factors downstream of cytokine receptors. Although STAT5A is expressed in most tissues it remains to be understood why its premier, non-redundant functions are restricted to prolactin-induced mammary gland development. We report that the ubiquitously expressed Stat5a/b locus is subject to lineage-specific transcriptional control in mammary epithelium. Genome-wide surveys of epigenetic status and transcription factor occupancy uncovered a putative mammary-specific enhancer within the intergenic sequences separating the two Stat5 genes. This region exhibited several hallmarks of genomic enhancers, including DNaseI hypersensitive sites, H3K27 acetylation and binding by GR and MED1. Mammary-specific STAT5 binding was obtained at two canonical STAT5 binding motifs. CRISPR/Cas9-mediated genome editing was used to delete these STAT5 binding sites in mice and determine their biological function. Mutant animals exhibited an 80% reduction of Stat5 levels in mammary epithelium and a concomitant reduction of STAT5-dependent gene expression. Transcriptome analysis identified a class of mammary-restricted genes that was particularly dependent on high STAT5 levels as a result of the intergenic enhancer. Taken together, the mammary-specific enhancer enables a positive feedback circuit that underlies the remarkable abundance of STAT5 and, in turn, controls the efficacy of STAT5-dependent mammary physiology.
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