Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

ZKSCAN3 in the transcriptional regulation of autophagy in human cells

ABSTRACT: Transcription factors can affect autophagy activity by promoting or inhibiting the expression of autophagy and lysosomal related genes. As a zinc finger family DNA-binding protein, ZKSCAN3 has been reported to function as a transcriptional repressor of autophagy, silencing of which can induced autophagy and promoted lysosome biogenesis in cancer cells. However, the studies in Zkscan 3 knockout mice showed that the deficiency of Zkscan3 did not induce autophagy and in-crease lysosome biogenesis. In order to further explore the role of ZKSCAN3 in the transcriptional regulation of autophagy in human cells, we generated ZKSCAN3 knockout HK-2 and Hela cells by CRISPR/Cas9 system and analyzed the differences in gene expression between ZKSCAN3 deleted cells and non-deleted cells through fluorescence quantitative PCR, Western blot and transcriptome sequencing, with special attention to the differences in gene expression of autophagy and lysosomal biogenesis. We found that ZKSCAN3 is not an essential regulator of autophagic or lysosomal gene expression, as the absence ZKSCAN3 had no significantly effect on the expression of autophagy or lysosomal genes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE218727 | GEO | 2023/01/31

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Cathepsin B modulates lysosomal biogenesis and host defense against Francisella novicida infection

Project description:Lysosomal cathepsins regulate an exquisite range of biological functions, and their deregulation is associated with inflammatory, metabolic and degenerative disease in humans. Here, we identified a key cell-intrinsic role for cathepsin B as a negative feedback regulator of lysosomal biogenesis and autophagy. Mice and macrophages lacking cathepsin B activity had increased resistance to the cytosolic bacterial pathogen Francisella novicida. Genetic deletion or pharmacological inhibition of cathepsin B downregulated mTOR activity and prevented cleavage of the lysosomal calcium channel TRPML1. These events drove transcription of lysosomal and autophagy genes via the transcription factor TFEB, which increased lysosomal biogenesis and activation of autophagy-initiation kinase ULK1 for clearance of the bacteria. Our results identified a fundamental biological function of cathepsin B in providing a checkpoint for homeostatic maintenance of lysosome population and basic recycling functions in the cell. We used microarrays to explore the gene expression profiles differentially expressed in bone marrow-derived macrophages (BMDM) isolated from cathepsin B-/- and wild-type mice.

2016-08-04 | E-GEOD-79508 | biostudies-arrayexpress

Human ZKSCAN3 and Drosophila M1BP are functionally homologous transcription factors in autophagy regulation

Project description:Autophagy is an essential cellular process that maintains homeostasis by recycling damaged organelles and nutrients during development and cellular stress. ZKSCAN3 is the sole identified master transcriptional repressor of autophagy in human cell lines. How ZKSCAN3 achieves autophagy repression at the mechanistic or organismal level however still remains to be elucidated. Furthermore, Zkscan3 knockout mice display no discernable autophagy-related phenotypes, suggesting that there may be substantial differences in the regulation of autophagy between normal tissues and tumor cell lines. Here, we demonstrate that vertebrate ZKSCAN3 and Drosophila M1BP are functionally homologous transcription factors in autophagy repression. Expression of ZKSCAN3 in Drosophila prevents premature autophagy onset due to loss of M1BP function and conversely, M1BP expression in human cells can prevent starvation-induced autophagy due to loss of nuclear ZKSCAN3 function. In Drosophila ZKSCAN3 binds genome-wide to sequences targeted by M1BP and transcriptionally regulates the majority of M1BP-controlled genes, demonstrating the evolutionary conservation of the transcriptional repression of autophagy and allow the potential for transitioning the mechanisms, gene targets and plethora metabolic processes controlled by M1BP onto ZKSCAN3 and opens up Drosophila as a tool in studying the function of ZKSCAN3 in autophagy and tumourigenesis.

2020-06-22 | GSE149116 | GEO

RNA-Seq Samples of siTFE3 in 8988T PDA Cell Line to Investigate Transcriptional Control of the Autophagy-Lysosome System

Project description:The activation of cellular quality control pathways to maintain metabolic homeostasis and mitigate diverse cellular stresses is emerging as a critical growth and survival mechanism in many cancers. Autophagy, a highly conserved cellular self-degradative process, is a key player in the initiation and maintenance of pancreatic ductal adenocarcinoma (PDA). However, the regulatory circuits that activate autophagy, and how they enable reprogramming of PDA cell metabolism are unknown. We now show that autophagy regulation in PDA occurs as part of a broader program that coordinates activation of lysosome biogenesis, function and nutrient scavenging, through constitutive activation of the MiT/TFE family of bHLH transcription factors. In PDA cells, the MiT/TFE proteins - MITF, TFE3 and TFEB - override a regulatory mechanism that controls their nuclear translocation, resulting in their constitutive activation. By orchestrating the expression of a coherent network of genes that induce high levels of lysosomal catabolic function, the MiT/TFE factors are required for proliferation and tumorigenicity of PDA cells. Importantly, unbiased global metabolite profiling reveals that MiT/TFE-dependent autophagy-lysosomal activation is specifically required to maintain intracellular AA pools in PDA. This AA flux is part of a program that is essential for metabolic homeostasis and bioenergetics of PDA but not for their non-transformed counterparts. These results identify the MiT/TFE transcription factors as master regulators of the autophagy-lysosomal system in PDA and demonstrate a central role of the autophagosome-lysosome compartment in maintaining tumor cell metabolism through alternative amino acid acquisition and utilization. Examination of mRNA levels in pancreatic ductal adenocarcinoma (PDA) cell line 8988T after treatment with siRNA for control or TFE3

2015-04-03 | E-GEOD-62077 | biostudies-arrayexpress

Cathepsin B modulates lysosomal biogenesis and host defense against Francisella novicida infection

2016-08-04 | GSE79508 | GEO

Mycobacterium tuberculosis resides in lysosome-poor monocyte-derived lung cells during chronic infection

Project description:Mycobacterium tuberculosis (Mtb) infects multiple lung myeloid cell subsets and persists despite innate and adaptive immune responses. However, the mechanisms allowing Mtb to evade elimination by these subsets are not fully understood. Here, we determined that four weeks post infection, after development of adaptive immune responses, CD11clo monocyte-derived lung cells termed MNC1 (mononuclear cell subset 1), harbor more live Mtb compared to alveolar macrophages (AM), neutrophils, and less permissive CD11chi MNC2. Bulk RNA-seq analysis for these subsets identified that lysosome biogenesis pathway is underexpressed in MNC1. Functional assays confirmed that Mtb-permissive MNC1 are deficient in lysosome content, lysosomal acidification, and lysosomal activity compared to AM, and have less nuclear TFEB, a master regulator of lysosome biogenesis. Mtb infection does not alter lysosome deficiency in MNC1. Instead, Mtb recruits MNC1 and MNC2 to the lungs for its spread from AM to these subsets, which depend on Mtb ESX-1 secretion system. Furthermore, nilotinib-mediated TFEB activation enhances lysosome function of primary macrophages in vitro, and MNC1 and MNC2 in vivo, improving control of Mtb infection. Our results suggest that Mtb exploits lysosome-poor monocyte-derived lung cells for persistence; targeting lysosome biogenesis may be an effective approach to host-directed therapy for tuberculosis, enabling permissive lung cells to restrict and kill Mtb through autophagy and other mechanisms.

2023-02-08 | GSE220147 | GEO

Transcriptome profiling based on the presence of Usf2 and nutrient starvation

Project description:Intricate regulation of lysosome and autophagy processes is essential for maintaining cellular homeostasis and basal metabolism. While the consequences of disrupting or attenuating lysosome and autophagy systems have been extensively studied, little is known about the impact of hyper-activation of lysosomal and autophagy genes on homeostasis. Our research uncovers previously unknown transcriptional repression mechanism by upstream stimulatory factor 2 (USF2), which inhibits lysosomal and autophagy genes in nutrient-rich conditions. USF2 binds to the CLEAR motif within lysosomal genes along with HDAC1, which diminishes H3K27 acetylation levels, restrains chromatin accessibility, and lowers lysosomal gene expression. Under starvation, USF2 competes with TFEB, a master transcriptional activator of lysosomal and autophagy genes, to bind target gene promoters in phosphorylation-dependent manner. Phosphorylation of the S155 site by GSK3b plays a pivotal role in controlling USF2's DNA binding activity for the repression of lysosomal genes while GSK3b-mediated phosphorylation of TFEB enhances its cytoplasmic retention. Applying these discoveries has potential for treating diseases associated with protein aggregation, including alpha-1 antitrypsin deficiency. These findings demonstrate that the USF2 repression mechanism could be a potent therapeutic strategy for various lysosome and autophagy-related diseases.

2024-08-06 | GSE252311 | GEO

Genome binding/occupancy profiling of USF2 under glucose starvation and changes in H3K27ac based on the presence of USF2

2024-08-06 | GSE252310 | GEO

chromatin accessibility profiling by ATAC-seq based on the presence of Usf2

2024-08-06 | GSE252309 | GEO

A cascade for zinc mediated transcriptional activation by the zinc-sensing nuclear receptor HIZR-1 on the regulator of lysosome biogenesis HLH-30 to achieve homeostasis

Project description:Zinc is an essential element for animals and stored in de novo synthesized lysosome related organelles called bilobed granules in Caenorhabditis elegans. Defining how zinc regulated transcription drives the observed lysosome remodeling is key to understand zinc homeostasis processes. Here we describe a positively regulated zinc network controlled by HIZR-1 and HLH-30, the zinc sensor and the master regulator of the autophagy-lysosomal pathway in Caenorhabditis elegans, respectively; essential for connecting zinc homeostasis to lysosome biogenesis. Our studies indicate that either hizr-1 and hlh-30 are necessary and sufficient to activate transcription of lysosome-genes under high dietary zinc conditions. Consistent with the hizr-1 and hlh-30 dependency for high zinc response, we found DNA enhancer elements corresponding to the high zinc activation element consistently adjacent to E-boxes in the promoter regions of lysosome-genes. We defined a regulatory network based on the contribution of each transcription factor. Since zinc cannot be degraded, the autophagy-lysosomal pathway could play a key role in removing zinc excess

2021-05-15 | GSE172079 | GEO

Enhanced and selective translation expands the lysosome size and promotes antigen presentation during phagocyte activation

Project description:The mechanisms that govern organelle remodeling remain poorly defined. Lysosomes degrade cargo from various routes including endocytosis, phagocytosis and autophagy. For phagocytes, lysosomes are a kingpin organelle since they are essential to kill pathogens and process and present antigens. During phagocyte activation, lysosomes undergo a striking reorganization, changing from dozens of globular structures to a tubular network, in a process that requires the phosphatidylinositol-3-kinase-AKT-mTOR signalling pathway. Here, we show that lysosomes undergo a remarkable expansion in volume and holding capacity during phagocyte activation within 2 h of LPS stimulation. Lysosome expansion was paralleled by an increase in lysosomal protein levels, but this was unexpectedly independent of TFEB and TFE3 transcription factors, known to scale up lysosome biogenesis. Instead, we demonstrate a hitherto unappreciated mechanism of acute organelle expansion via mTORC1-dependent increase in translation of mRNAs encoding key lysosomal proteins. Importantly, mTORC1-dependent increase in translation activity was necessary for efficient and rapid antigen presentation by dendritic cells. Collectively, we identified a previously unknown and functionally relevant mechanism for lysosome expansion that relies on mTORC1-dependent enhanced translation of mRNAs to boost protein synthesis and lysosome biogenesis in response to an infection signal.

2020-01-07 | GSE136470 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data