Remodeling of Zn2+ Homeostasis Upon Differentiation of Mammary Epithelial Cells
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE144160 | GEO | 2020/01/24
REPOSITORIES: GEO
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Project description:Remodeling of Zn2+ Homeostasis Upon Differentiation of Mammary Epithelial Cells
| PRJNA602910 | ENA
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.
| S-EPMC7135929 | biostudies-literature
Project description:Purpose: Understanding of gene transcriptional networks specifying murine mammary epithelial cells (HC11) during lactogenic differentiation and its comparision with murine embryonic stem cells Methods: RNA-sequencing after ribosomal RNA depletion followed by cDNA synthesis, adaptor ligation and sequencing in duplicate of each sample using Illumina Hi-seq 2500 paired end sequencing. Sequence reads with adapters, over-represented and low-quality reads were discarded. High quality reads were mapped to reference mouse genome (mm10) using Bowtie followed derivation of FPKM values using cufflinks and DE-seq to observe differentially expressed genes. Results: Using standard analysis methods which were published recently we uniquely mapped more than 50 million sequence reads out of which total 11961 transcripts were from ESC, 11045 from Normal, 11243 from Primed and 10719 from prolactin stage. When we did DE-seq differential gene expression analysis we observed that for Normal to primed transition 1141 and 1026 transcripts were Up and Down regulated respectively where as upon transition from Primed to Prolactin stage 385 and 655 transcripts were Up and Down regulated respectively. We also did pathway analysis to interpret the transcript activation and its function during lactogeinc differentiation; we found that the pathways which are highly up regulated are related to carbohydrate, lipids, nucleic acid and protein metabolism. We also observed that most of the up regulated pathways were related to maintenance of mammary cells differentiated state and nutrition of the infants. Our study concludes that overall differentiation requires priming with glucocorticoids followed by prolactin stimulation of HC11 cells, which tunes the cells for the secretion of milk and its maintenance of the differentiated state till the lactation period. Conclusions: Transcriptome analysis by next generation sequencing allowed us to explore global gene expression during lactogenic differentiation of HC11 cells in presence of glucocortiocids in primed state. Glucocorticoids are activating genes, transcription factors, epigenetic modifiers and metabolic pathways which are required for later stages of lactation. On other hand gene expression analysis of prolactin stage revealed that there is a focused gene expression exclusively related to lactation process. We also observed that HC11 stem like marker are highly expressed in undifferentiated state whose expression was down regulated in primed and prolactin state indicating that HC11 are partially bipotent cells; when these cells receive differentiation signals they loose their stem cell like characteristics and are differentiated.
2018-02-09 | GSE107419 | GEO
Project description:PAPAS is an antisense transcript of rRNA genes and mediates silencing of the locus in non-dividing cells. Here, we have analyzed PAPAS function in lactogenic differentiation of mammary epithelial cells (HC11 cells) and in mammary cancer cells (4T1). Using doxycycline (Dox) inducible shRNA against PAPAS, we found that the knockdown perturbs differentiation and inhibits expression of lactogenic genes. In contrast, Dox-inducible overexpression of PAPAS in 4T1 cells suppresses genes required for ribosome biogenesis and slows down the neoplastic growth.
2024-01-01 | GSE218723 | GEO
Project description:Using our unique and authentic animal model, the pig, we determined which genes in the normal mammary gland are regulated in response to different combinations of the ovarian hormones estrogen and progesterone and the pituitary hormone prolactin. We surgically removed ovaries from 32 pigs to deplete endogenous estrogen and progesterone, and administered bromocriptine to suppress endogenous prolactin. Pigs were treated with all combinations of estrogen, progesterone and bromocriptine and/or haloperidol (to induce prolactin secretion), in a factorial design. Affymetrix arrays were used to analyze RNA from the mammary glands of these pigs and we found that estrogen, prolactin and the interaction of estrogen*prolactin were the primary regulators of gene expression in the mammary gland. This is in contrast to rodents where progesterone has an important role in ductal elongation and branching. Functional enrichment analyses suggest that estrogen promotes cell division while prolactin stimulates elements of fatty acid metabolism and an inflammatory response (in addition to milk protein genes). These results concur with phenotypic changes where estrogen, prolactin and estrogen*prolactin were the most important regulators of morphological development, cell proliferation and steroid receptor expression. Regression analysis of expression data against the rate of cell proliferation in all 32 pigs identified 1669 genes correlated with proliferation (FDR a=0.01). Regression analysis of expression data against proliferation in the 16 pigs treated with E identified 71 genes correlated with proliferation. 29 genes were common to both lists and also regulated by estrogen, and of these 16 have known functions in the cell cycle while the other 13 have never been associated with estrogen regulated mammary gland growth or cell proliferation. Twenty six of these genes were more highly correlated with proliferation than MKI67 (Ki67).
2020-10-25 | GSE106212 | GEO
Project description:Major Depression (MDD) is a prevalent psychiatric disorder and exposure to stress is robust risk factor for MDD. Clinical data and rodent models have indicated the negative impact of chronic stress induced hormones like cortisol on brain volume, memory, and cell metabolism. However, the cellular and transcriptomic changes that occur in the brain after prolonged exposure to cortisol are less understood. Furthermore, astrocyte-specific contribution to cortisol-induced neuropathology remains understudied. Here, we have developed an in vitro model of “chronic stress” using human induced pluripotent stem cell-derived astrocytes treated with cortisol for 7 days. Whole transcriptome sequencing reveals differentially expressed genes (DEGs) uniquely regulated in chronic cortisol compared to acute cortisol treatment. Utilizing this paradigm, we examined the stress response transcriptome of astrocytes generated from MDD patient iPSCs. MDD-specific DEGs related to GPCR ligand binding, synaptic signaling, and ion homeostasis. Together, these data highlight the unique role astrocytes play in the central nervous system and present interesting genes for future study into the relationship between chronic stress and MDD.
2022-10-04 | GSE178071 | GEO
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
Project description:Pancreatic islets adapt to the increase in insulin demand during pregnancy by up-regulating beta cell proliferation, insulin synthesis, and lowering the threshold of glucose-stimulated insulin secretion. In vitro studies suggest that pregnancy hormones, such as placental lactogens and prolactin, both act through the prolactin receptor, are required for these adaptation. Furhtermore, we found that transgenic mice with heterogenous prolactin receptor null mutation are glucose intolerant, with a lower beta-cell mass and lower insulin levels. The goal here is to discover novel targets of prolactin receptor signaling in pancreatic beta cells during pregnancy.
2019-02-01 | GSE125350 | GEO
Project description:The GATA-type zinc-finger transcription factor TRPS1 has been implicated in breast cancer. However, its precise role remains unclear, as both amplifications and inactivating mutations in TRPS1 have been reported. Here, we used in vitro and in vivo loss-of-function approaches to dissect the role of TRPS1 in mammary gland development and invasive lobular breast carcinoma, which is hallmarked by functional loss of E-cadherin. We show that TRPS1 is essential in mammary epithelial cells, since TRPS1-mediated suppression of interferon signaling promotes in vitro proliferation and lactogenic differentiation. Similarly, TRPS1 expression is indispensable for proliferation of mammary organoids and in vivo survival of luminal epithelial cells during mammary gland development. However, the consequences of TRPS1 loss are dependent on E-cadherin status, as combined inactivation of E-cadherin and TRPS1 causes persistent proliferation of mammary organoids and accelerated mammary tumor formation in mice. Together, our results demonstrate that TRPS1 can function as a context-dependent tumor suppressor in breast cancer, whilst being essential for growth and differentiation of normal mammary epithelial cells.
2019-12-05 | GSE133074 | GEO
Project description:The GATA-type zinc-finger transcription factor TRPS1 has been implicated in breast cancer. However, its precise role remains unclear, as both amplifications and inactivating mutations in TRPS1 have been reported. Here, we used in vitro and in vivo loss-of-function approaches to dissect the role of TRPS1 in mammary gland development and invasive lobular breast carcinoma, which is hallmarked by functional loss of E-cadherin. We show that TRPS1 is essential in mammary epithelial cells, since TRPS1-mediated suppression of interferon signaling promotes in vitro proliferation and lactogenic differentiation. Similarly, TRPS1 expression is indispensable for proliferation of mammary organoids and in vivo survival of luminal epithelial cells during mammary gland development. However, the consequences of TRPS1 loss are dependent on E-cadherin status, as combined inactivation of E-cadherin and TRPS1 causes persistent proliferation of mammary organoids and accelerated mammary tumor formation in mice. Together, our results demonstrate that TRPS1 can function as a context-dependent tumor suppressor in breast cancer, whilst being essential for growth and differentiation of normal mammary epithelial cells.
2019-12-05 | GSE133072 | GEO