Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA307593 | ENA |
REPOSITORIES: ENA
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Project description:Only a small number of genes are known direct targets of the zinc-responsive transcription factor MTF1; therefore, the aim of this study was to gain a more complete understanding of the MTF-1 regulated zinc-responsive component of the transcriptome. A targeted siRNA was used to deplete MTF1 expression in the human intestinal cell line Caco-2. We predicted that the response to zinc of direct MTF1 target genes would be abrogated by MTF1 knockdown. Surprisingly, a greater number of genes were regulated by zinc following MFT1 knockdown, and most genes that responded to zinc under both control and MTF1-depleted conditions had an augmented response in the latter condition. Exceptions were the zinc effluxer ZnT1 and a suite of metallothionein genes, suggesting that responses of other genes to zinc are usually buffered by increases in these proteins. We propose that MTF1 heads a hierarchy of zinc sensors, and through controlling the expression of a raft of metallothioneins and other key proteins involved in controlling intracellular zinc levels (e.g. ZnT1) alters zinc buffering capacity and total cellular zinc content. We tested and validated this model by overexpressing metallothionein and observing the predicted curtailment in response of the zinc-repressed SLC30A5 (ZnT5) promoter. The model provides the framework for an integrated understanding of cellular zinc homeostasis. Because MTs can bind metals other than zinc, this framework links with overall cellular metal homeostasis. Gene expression profiling by Illumina BeadArray of the effects of ZNF658 gene knockdown by siRNA. 2 different siRNAs were used, with appropriate non-targetting controls. All experiments were carried out in triplicate.
2016-02-24 | E-GEOD-76510 | biostudies-arrayexpress
Project description:Only a small number of genes are known direct targets of the zinc-responsive transcription factor MTF1; therefore, the aim of this study was to gain a more complete understanding of the MTF-1 regulated zinc-responsive component of the transcriptome. A targeted siRNA was used to deplete MTF1 expression in the human intestinal cell line Caco-2. We predicted that the response to zinc of direct MTF1 target genes would be abrogated by MTF1 knockdown. Surprisingly, a greater number of genes were regulated by zinc following MFT1 knockdown, and most genes that responded to zinc under both control and MTF1-depleted conditions had an augmented response in the latter condition. Exceptions were the zinc effluxer ZnT1 and a suite of metallothionein genes, suggesting that responses of other genes to zinc are usually buffered by increases in these proteins. We propose that MTF1 heads a hierarchy of zinc sensors, and through controlling the expression of a raft of metallothioneins and other key proteins involved in controlling intracellular zinc levels (e.g. ZnT1) alters zinc buffering capacity and total cellular zinc content. We tested and validated this model by overexpressing metallothionein and observing the predicted curtailment in response of the zinc-repressed SLC30A5 (ZnT5) promoter. The model provides the framework for an integrated understanding of cellular zinc homeostasis. Because MTs can bind metals other than zinc, this framework links with overall cellular metal homeostasis.
2016-02-24 | GSE76510 | GEO
Project description:Zinc (Zn) is widely recognized as an essential diet-derived micronutrient for optimal growth due to its crucial role in cell proliferation, differentiation, and apoptosis[1-3]. Yet the precise role of Zn in barrier sites such as the intestinal epithelium that is constantly renewing and remodeling remains poorly defined. To address how Zn impacts epithelial lining and gut homeostasis, we generated mice defective in Zn sensing by deleting Metal-responsive Transcription Factor 1 (MTF1) specifically in the intestinal epithelial cells (IECs). MTF1 is a highly conserved Zn-dependent transcription factor that regulates cellular Zn homeostasis [4]. Mice deleted for MTF1 in intestinal epithelial cells (MTF1 ΔIEC) had altered Zn homeostasis that coincided with significant increase in inflammatory immune response to microbes, indicating a critical role of IEC intrinsic Zn sensing in regulating immune homeostasis in the gut. MTF1 deletion resulted in loss of specialized secretory cell lineages such as Paneth and Tuft cells, compromised barrier function against commensal bacteria, and altered susceptibility to helminth and viral infections. MTF1-dependent Zn sensing proved essential for differentiating specialized epithelial cell lineages from newly proliferated intestinal stem cells. Ex vivo experiments using small intestinal organoids (SIOs) demonstrated that Zn treatment promoted the differentiation of proliferating epithelial cells into specialized cell lineages in wild-type organoids, an effect which is absent in MTF1ΔIEC SIOs. This study provides compelling evidence for the fundamental role of Zn in promoting the differentiation of specialized intestinal epithelial cell lineages, which are key to interactions with diverse microbes and maintaining immune homeostasis in the gut.
2025-06-24 | GSE284340 | GEO
Project description:Zinc (Zn) is widely recognized as an essential diet-derived micronutrient for optimal growth due to its crucial role in cell proliferation, differentiation, and apoptosis[1-3]. Yet the precise role of Zn in barrier sites such as the intestinal epithelium that is constantly renewing and remodeling remains poorly defined. To address how Zn impacts epithelial lining and gut homeostasis, we generated mice defective in Zn sensing by deleting Metal-responsive Transcription Factor 1 (MTF1) specifically in the intestinal epithelial cells (IECs). MTF1 is a highly conserved Zn-dependent transcription factor that regulates cellular Zn homeostasis [4]. Mice deleted for MTF1 in intestinal epithelial cells (MTF1 ΔIEC) had altered Zn homeostasis that coincided with significant increase in inflammatory immune response to microbes, indicating a critical role of IEC intrinsic Zn sensing in regulating immune homeostasis in the gut. MTF1 deletion resulted in loss of specialized secretory cell lineages such as Paneth and Tuft cells, compromised barrier function against commensal bacteria, and altered susceptibility to helminth and viral infections. MTF1-dependent Zn sensing proved essential for differentiating specialized epithelial cell lineages from newly proliferated intestinal stem cells. Ex vivo experiments using small intestinal organoids (SIOs) demonstrated that Zn treatment promoted the differentiation of proliferating epithelial cells into specialized cell lineages in wild-type organoids, an effect which is absent in MTF1ΔIEC SIOs. This study provides compelling evidence for the fundamental role of Zn in promoting the differentiation of specialized intestinal epithelial cell lineages, which are key to interactions with diverse microbes and maintaining immune homeostasis in the gut.
2025-06-24 | GSE284341 | GEO
Project description:Thioneins are cysteine-rich, evolutionary conserved apoproteins that regulate divalent metal homeostasis by virtue of their metal-chelation properties resulting in the ligand-bound metallothionein state. Previous studies have demonstrated a transient upregulation (102- 103-fold) of a cluster of metallothionein genes as part of a transcriptional response to a class of histone demethylase tool compounds targeting human Fe2+ dependent ketoglutarate oxygenases KDM6A (UTX) and KDM6B (JmjD3). Exposure of multiple myeloma cells to the prototypic bioactive KDM6 inhibitor GSK-J4 induces apoptotic cell death and transcriptomic profiles that are dominated by metal and metabolic stress response signatures. We here investigate the hypothesis that the metal-chelating property of GSK-J4 provides the means for transport and intracellular release of Zn2+ leading to a metallothionein transcriptomic response signature. Live cell imaging upon myeloma cell exposure to GSK-J4 shows a transient increase of intracellular free Zn2+ concentrations upon KDM6 inhibitor treatment consistent with a model of inhibitor mediated metal transport. Comparison of KDM6 inhibitor and ZnSO4 treatments in the presence or absence of metal chelators show that both treatment conditions induce different transcription factor repertoires with an overlapping MTF1 transcriptional regulation responsible for metallothionein and metal ion transport regulation.
2022-09-16 | GSE213291 | GEO
Project description:Thioneins are cysteine-rich, evolutionary conserved apoproteins that regulate divalent metal homeostasis by virtue of their metal-chelation properties resulting in the ligand-bound metallothionein state. Previous studies have demonstrated a transient upregulation (102- 103-fold) of a cluster of metallothionein genes as part of a transcriptional response to a class of histone demethylase tool compounds targeting human Fe2+ dependent ketoglutarate oxygenases KDM6A (UTX) and KDM6B (JmjD3). Exposure of multiple myeloma cells to the prototypic bioactive KDM6 inhibitor GSK-J4 induces apoptotic cell death and transcriptomic profiles that are dominated by metal and metabolic stress response signatures. We here investigate the hypothesis that the metal-chelating property of GSK-J4 provides the means for transport and intracellular release of Zn2+ leading to a metallothionein transcriptomic response signature. Live cell imaging upon myeloma cell exposure to GSK-J4 shows a transient increase of intracellular free Zn2+ concentrations upon KDM6 inhibitor treatment consistent with a model of inhibitor mediated metal transport. Comparison of KDM6 inhibitor and ZnSO4 treatments in the presence or absence of metal chelators show that both treatment conditions induce different transcription factor repertoires with an overlapping MTF1 transcriptional regulation responsible for metallothionein and metal ion transport regulation.
2022-09-16 | GSE213292 | GEO
Project description:MTF1 is a highly conserved metal-binding transcription factor in eukaryotes. MTF1 binds to DNA sequence motifs, termed metal response elements (MREs) to induce the expression of genes involved in metal and oxidative stress homeostasis. MTF1 is responsive to both metal excess and deprivation, and can also protect cells from oxidative and hypoxic stresses. Disruption of metal homeostasis leads to the development of several pathological states. Despite its roles in these processes , MTF1 has been shown to be required for developmental processes such as embryonic liver formation. In this study, we used multiple strategies to understand the mechanism by which MTF1 functions in skeletal muscle differentiation and to determine the role cellular copper (Cu) status plays in this process. We provide the functional relationships between MTF1, Cu, myogenic gene promoters, and MyoD, an specific component of the myogenic transcriptional machinery in differentiating primary myoblasts derived from mouse satellite cells. We found that MTF1 is induced and translocated to the nucleus upon initiation of myogenesis. Consistent with previous studies from our laboratory , addition of non-toxic concentrations of Cu promote myogenesis and enhanced MTF1 expression. CRISPR/Cas9-mediated depletion of MTF1 demonstrated that MTF1 is essential for proper development of skeletal muscle, as partial Mtf1 knockdown leads to apoptosis to differentiating myoblasts. MTF1 was also found to bind Cu at a carboxy-terminal tetra-cysteine cluster, which may contribute to the mobilization of Cu to the nucleus during myogenesis. ChIP-seq and ChIP-qPCR analyses showed that MTF1 binds at the promoter regions of myogenic genes as part of a complex with MyoD, the master transcriptional regulator of the myogenic lineage. These results have the potential to initiate a new area of research in MTF1 function and in the regulation of myogenesis. Furthermore, these studies set the basis to understand the role of Cu at the transcriptional level, affects growth and development and will contribute to the largely unexplored are of muscular phenotypes observed in human pathologies associated to Cu misbalance, such as Menkes’ and Wilson’s diseases.
2019-10-04 | GSE116331 | GEO
Project description:Copper and MTF1: New roles for a classic metal sensing transcription factor in myogenesis
| PRJNA478204 | ENA
Project description:Huntington’s disease (HD) is an inherited and incurable neurodegenerative disorder caused by CAG repeat expansions in the huntingtin (HTT) gene. The resulting mutant HTT protein alters cellular physiology at multiple levels, inducing toxicity and cell death. The mechanisms directly causing toxicity are partially understood, thus precluding the development of effective therapeutic strategies. Here we identified novel suppressors of mutant HTT toxicity by performing a genome-wide screen in pluripotent stem cells, followed by hit validation both in zebrafish and mouse HD models. The candidate suppressors identified were strongly enriched for HD-associated processes. We focused on Metal regulatory transcription factor 1 (Mtf1), a transcription factor controlling metal homeostasis in the cell. Forced expression of Mtf1 counteracts cell death, oxidative stress and transcriptional alterations caused by mutant HTT in pluripotent cells. In zebrafish, Mtf1 reduces malformations and apoptosis induced by mutant HTT, while Mtf1 delivery by Adeno-Associated viral (AAV) vectors ablated motor defects observed in an HD mouse model. Our data reveal that delivery of Mtf1 might act as a novel therapeutic strategy against HD and potentially other neurodegenerative disorders.
2023-05-30 | GSE166567 | GEO
Project description:Zinc is an essential divalent trace metal for living cells. Intracellular zinc homeostasis is critical to the pathogenicity and virulence of bacteria, however the strategies of zinc homeostasis maintain in Streptococcus mutans, an important causative pathogen of dental caries, is unknown. In this study, we examined the function of an ABC transporter AdcCBA and its transcription factor AdcR in S. mutans. Using RNA-Seq analysis, LacZ-reporter studies and gel mobility shift assay, we showed that a MarR family transcription factor AdcR directly regulates the activity of promoters of adcRCB and adcA in response to the concentration of zinc in their environmental niches. Deletion of adcR increases the sensitivity of S. mutans to excessive zinc supply. Taken together, our finding suggests that Adc regulon, consists of a zinc uptake transporter AdcCBA and a zinc-responsive repressor AdcR, plays a prominent role in the maintenance of intracellular zinc homeostasis of S. mutans.
2021-07-01 | GSE165796 | GEO