Remodeling of Zn2+ Homeostasis Upon Differentiation of Mammary Epithelial Cells
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ABSTRACT:
PROVIDER: PRJNA602910 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10959100.fastq.gz | Fastqsanger.gz | |||
| SRR10959100_1.fastq.gz | Fastqsanger.gz | |||
| SRR10959100_2.fastq.gz | Fastqsanger.gz | |||
| SRR10959101_1.fastq.gz | Fastqsanger.gz | |||
| SRR10959101_2.fastq.gz | Fastqsanger.gz |
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Project description:Using mouse mammary epithelial cells as a model system, we investigated the remodeling of zinc homeostasis during differentiation induced by treatment with the lactogenic hormones cortisol and prolactin. RNA-Seq at different stages of differentiation revealed changes in global gene expression, including genes encoding zinc-dependent proteins and regulators of zinc homeostasis. Increases in mRNA levels of three zinc homeostasis genes,.
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Project description:Baroreflex control of cardiac contraction (positive inotropy) through sympathetic nerve activation is important to maintain cardiocirculatory homeostasis. Transient receptor potential canonical subfamily (TRPC) channels are responsible for alfa1-adrenoceptor (alfa1AR)-stimulated cation entry and their upregulation is reportedly associated with pathological cardiac remodeling, but whether TRPC channels participate in physiological pump functions remains unclear. Here, we demonstrate that TRPC6-specific Zn2+ influx potentiates alfa-adrenoceptor (alfaAR)-stimulated positive inotropy in rodent cardiomyocytes. Deletion of the trpc6 gene impairs sympathetic nerve-activated positive inotropy, but not chronotropy in mice. TRPC6-mediated Zn2+ influx boosts alfa1AR-stimulatedalfaAR/Gs-dependent signaling in rat cardiomyocytes by inhibiting alfa-arrestin-mediated alfaAR internalization. Replacing two TRPC6-specific amino acids in the pore region with those of TRPC3 diminishes the alfa1AR-stimulated Zn2+ influx and positive inotropic response. Pharmacological enhancement of TRPC6-mediated Zn2+ influx prevents the progression of heart failure in dilated cardiomyopathy mice. Our data provide evidence that TRPC6-mediated Zn2+ influx with α1AR stimulation enhances baroreflex-induced positive inotropy, which may be a new therapeutic strategy for chronic heart failure.
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Project description:Zinc (Zn2+) is an integral component of many proteins and has been shown to act in a regulatory capacity in different mammalian systems, including as a neurotransmitter in neurons throughout the brain. While Zn2+ plays an important role in modulating neuronal potentiation and synaptic plasticity, little is known about the signaling mechanisms of this regulation. In dissociated rat hippocampal neuron cultures, we used fluorescent Zn2+ sensors to rigorously define resting Zn2+ levels and stimulation-dependent intracellular Zn2+ dynamics, and we performed RNA-Seq to characterize Zn2+-dependent transcriptional effects upon stimulation. We found that relatively small changes in cytosolic Zn2+ during stimulation altered expression levels of 931 genes, and these Zn2+ dynamics induced transcription of many genes implicated in neurite expansion and synaptic growth. Additionally, while we were unable to verify the presence of synaptic Zn2+ in these cultures, we did detect the synaptic vesicle Zn2+ transporter ZnT3 and found it to be substantially upregulated by cytosolic Zn2+ increases. These results provide the first global sequencing-based examination of Zn2+-dependent changes in transcription and identify genes that may mediate Zn2+-dependent processes and functions.
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Project description:Tissue resident macrophages in the mammary gland are found in close association with epithelial structures and within the adipose stroma, and are important for mammary gland development and tissue homeostasis. While epithelial-associated macrophages have been linked to ductal development, the contributions of stromal macrophages to mammary gland homeostasis remain unknown. Using transcriptional profiling, we identify a distinct resident stromal macrophage subpopulation that is characterized by expression of Lyve-1, a receptor for the extracellular matrix component hyaluronan. This subpopulation is enriched in genes associated with extracellular matrix remodeling and is found to be specifically associated with hyaluronan-rich regions within the mammary stroma. Furthermore, macrophage depletion leads to increased accumulation of hyaluronan-associated extracellular matrix in the mammary stroma. These results demonstrate the presence of a distinct subpopulation of macrophages and provide insights into the functional contributions of these macrophages to stromal homeostasis in the mammary gland.
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Project description:Zinc is the second most abundant transition metal in humans and an essential nutrient required for growth and development of newborns. During lactation, mammary epithelial cells differentiate into a secretory phenotype, uptake zinc from blood circulation, and export it into mother's milk. At the cellular level, many zinc-dependent cellular processes, such as transcription, metabolism of nutrients, and proliferation are involved in the differentiation of mammary epithelial cells. Using mouse mammary epithelial cells as a model system, we investigated the remodeling of zinc homeostasis during differentiation induced by treatment with the lactogenic hormones cortisol and prolactin. RNA-Seq at different stages of differentiation revealed changes in global gene expression, including genes encoding zinc-dependent proteins and regulators of zinc homeostasis. Increases in mRNA levels of three zinc homeostasis genes, Slc39a14 (ZIP14) and metallothioneins (MTs) I and II were induced by cortisol but not by prolactin. The cortisol-induced increase was partially mediated by the nuclear glucocorticoid receptor signaling pathway. An increase in the cytosolic labile Zn2+ pool was also detected in lactating mammary cells, consistent with upregulation of MTs. We found that the zinc transporter ZIP14 was important for the expression of a major milk protein, whey acid protein (WAP), as knockdown of ZIP14 dramatically decreased WAP mRNA levels. In summary, our study demonstrated remodeling of zinc homeostasis upon differentiation of mammary epithelial cells resulting in changes in cytosolic Zn2+ and differential expression of zinc homeostasis genes, and these changes are important for establishing the lactation phenotype.
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Project description:Zinc (Zn2+) is an important trace metal ion that has been shown to regulate the expression of several (virulence) genes in streptococci. Previously, we analyzed the genome-wide response of S. pneumoniae to Zn2+-stress. In this work, we have performed a transcriptomic analysis to identify genes that are differentially expressed under intracellular Zn2+-limitation. This revealed a number of genes that are highly upregulated in the absence of extracellular Zn2+, amongst which the genes belonging to the regulon of the Zn2+-responsive repressor AdcR, like adcBCA, encoding a Zn2+-dependent ABC-uptake system, adcAII, encoding a Zn2+-binding lipoprotein, and also virulence genes belonging to the Pht family (phtA, phtB, phtD and phtE). Using transcriptome analysis, lacZ-reporter studies, in vitro DNA binding experiments, and in silico operator predictions, we show that AdcR directly represses the promoters of adcRCBA, adcAII-phtD, phtA, phtB and phtE in the presence of Zn2+. AdcR can also function as an activator, since in the presence of Zn2+ it directly induces expression of adh that encodes a Zn2+-containing alcohol dehydrogenase. In conclusion, the genome-wide transcriptional response of S. pneumoniae to Zn2+-limitation was established, which is mainly mediated via direct regulation by the Zn2+-dependent regulator AdcR. This SuperSeries is composed of the SubSeries listed below.
2011-05-13 | GSE29236 | GEO
Project description:Zinc (Zn2+) is an important trace metal ion that has been shown to regulate the expression of several (virulence) genes in streptococci. Previously, we analyzed the genome-wide response of S. pneumoniae to Zn2+-stress. In this work, we have performed a transcriptomic analysis to identify genes that are differentially expressed under intracellular Zn2+-limitation. This revealed a number of genes that are highly upregulated in the absence of extracellular Zn2+, amongst which the genes belonging to the regulon of the Zn2+-responsive repressor AdcR, like adcBCA, encoding a Zn2+-dependent ABC-uptake system, adcAII, encoding a Zn2+-binding lipoprotein, and also virulence genes belonging to the Pht family (phtA, phtB, phtD and phtE). Using transcriptome analysis, lacZ-reporter studies, in vitro DNA binding experiments, and in silico operator predictions, we show that AdcR directly represses the promoters of adcRCBA, adcAII-phtD, phtA, phtB and phtE in the presence of Zn2+. AdcR can also function as an activator, since in the presence of Zn2+ it directly induces expression of adh that encodes a Zn2+-containing alcohol dehydrogenase. In conclusion, the genome-wide transcriptional response of S. pneumoniae to Zn2+-limitation was established, which is mainly mediated via direct regulation by the Zn2+-dependent regulator AdcR. Two condition design comparison of Wild-type strain including a dye swap Refer to individual Series. This SuperSeries is composed of the following subset Series: GSE29234: adcR mutant vs wild type D39 GSE29235: Low Zn vs high Zn in CDM
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