RNA-seq analyses for control and nicotinamide treated TNBC cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE172494 | GEO | 2021/04/22
REPOSITORIES: GEO
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Project description:Ablation of expression of the Max gene encoding a Myc protein partner in ES cells provoked two major phenomena, i.e. loss of pluripotency and apoptotic cell death. We found that nicotinamide (Nam) significantly alleviates these Max expression ablation-coupled phenotypes in ES cells. To see the alleviation effect of Nam on the overall expression profile of Max-null ES cells whose Max expression is controlled by the tet-off system, we eliminated Max expression by adding doxycycline (Dox) in the presence of Nam.
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Project description:Acne vulgaris is a chronic inflammatory disease of the skin resulting from androgeninduced increased sebum production and altered keratinization. Nicotinamide (NAM), an amide form of vitamin B3 with a well-established safety profile, has shown good therapeutic potential in treating acne and its complications. NAM has anti-inflammatory effects and reduces sebum but its function in androgen biosynthesis remains unknown. In this study, we used a widely used cell model, starved human adrenal NCI-H295R cells, to examine the effects of NAM in androgen production and its mediated network changes. By treating NCI-H295R cells with 1-25 mmol/L of NAM, we found that cell viability was only slightly inhibited at the highest dose (25 mmol/L). NAM reduced testosterone production in a dose-dependent manner. Transcriptomic analysis demonstrated that key enzymes of androgen biosynthesis were significantly decreased under NAM treatment. In addition, gene set enrichment analysis (GSEA) showed that gene sets of cell cycle, steroid biosynthesis, TGFβ signalling, and targets of IGF1 or IGF2 were enriched in NAM-treated cells. Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway and Gene ontology (GO) analysis of the differentially expressed genes also suggested that steroidogenesis and SMAD signalling were affected by NAM. Overall, these crucial genes and pathways might form a complex network in NAM-treated NCI-H295R cells and result in androgen reduction. These findings help explain the potential molecular actions of NAM in acne vulgaris, and position NAM as a candidate for the treatment of other hyperandrogenic disorders.
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Project description:Mechanisms to control the immune response are important to pathogen evasion and host defense. Gram-negative bacteria are common pathogens that can activate host immune responses through their outer membrane component, lipopolysaccharide (LPS). Macrophages activated by LPS induce cell signals that promote hypoxic metabolism, phagocytosis, and antigen presentation. Nicotinamide (NAM) is a vitamin B3 derivative and precursor in the formation of nicotinamide adenine dinucleotide (NAD), which is a required co-factor in cellular function. In this study, treatment of human monocyte derived macrophages with NAM antagonized LPS-induced responses by altering the expression of ubiquitin genes, increasing HIF-1alpha and p65/RelA ubiquitination, decreasing p65/RelA acetylation and promoting the formation of the proteasome. NAM also elevated intracellular NAD levels and altered the genetic expression of sirtuins and poly(ADP-ribose) polymerases. These NAM responses highlight post-translational events in regulating the host response to pathogens and identify the ubiquitome as a target in pathogen evasion and host defense.
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Project description:Sirtuin deacetylases and forkhead box class O (FOXO) transcription factors are central regulators of cell survival, cell cycle and cellular resistance to stress in response to signals from hormones, growth factors and oxidative stress. FOXO activity is modulated by the sirtuins, which function in a NAD+-dependent manner. Sirtuin activity, on the other hand is subject to inhibition by a natural compound nicotinamide (NAM). This study aims to investigate the effects of NAM on the sirtuin pathway and cellular homeostasis. It was hypothesized that NAM inhibits the sirtuin deacetylase activity, which then shifts FOXO-dependent responses away from stress resistance and towards apoptosis. Expression analysis using Affymetrix microarray was employed to determine differential gene expression in HEK293 cells in response to NAM treatment. Data analyses were performed using multiple algorithms, computational methods and interaction analyses. Significant changes in gene expression were detected with the generation of an expansive list of genes and interaction amongst gene groups were identified from the NAM treatment at different concentration. Substantial changes in expression profiles were detected for genes involved in a number of unique cellular pathways and functions, including cell cycle arrest, cellular proliferation and differentiation, metabolism, apoptotic signaling, inflammatory regulation and various disease conditions such as cancer. In addition, this study observed that sirtuin activities exhibit complex cell- and contextdependent behavior in modulating FOXO signaling. Contrasting roles of FOXOs and sirtuins appear to have opposite effects on cellular homeostasis. In addition, the coexistence of reciprocal regulations in this cell system suggested several levels of feedback control and illustrated the complexity of an existing fine-tuned regulatory network system between these two proteins. Future work aims to characterize putative regulators and effectors of sirtuin- and FOXO-related pathways using molecular approaches such and RNA interference knockdown of individual FOXO-isoforms. Inter-connectivity of the pathways will provide invaluable insight into current understanding of cell degeneration diseases such as diabetes, cancers and neurological disorders. Keywords: Serial concentration experiment
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Project description:Sirtuin deacetylases and forkhead box class O (FOXO) transcription factors are central regulators of cell survival, cell cycle and cellular resistance to stress in response to signals from hormones, growth factors and oxidative stress. FOXO activity is modulated by the sirtuins, which function in a NAD+-dependent manner. Sirtuin activity, on the other hand is subject to inhibition by a natural compound nicotinamide (NAM). This study aims to investigate the effects of NAM on the sirtuin pathway and cellular homeostasis. It was hypothesized that NAM inhibits the sirtuin deacetylase activity, which then shifts FOXO-dependent responses away from stress resistance and towards apoptosis. Expression analysis using Affymetrix microarray was employed to determine differential gene expression in HEK293 cells in response to NAM treatment. Data analyses were performed using multiple algorithms, computational methods and interaction analyses. Significant changes in gene expression were detected with the generation of an expansive list of genes and interaction amongst gene groups were identified from the NAM treatment at different concentration. Substantial changes in expression profiles were detected for genes involved in a number of unique cellular pathways and functions, including cell cycle arrest, cellular proliferation and differentiation, metabolism, apoptotic signaling, inflammatory regulation and various disease conditions such as cancer. In addition, this study observed that sirtuin activities exhibit complex cell- and contextdependent behavior in modulating FOXO signaling. Contrasting roles of FOXOs and sirtuins appear to have opposite effects on cellular homeostasis. In addition, the coexistence of reciprocal regulations in this cell system suggested several levels of feedback control and illustrated the complexity of an existing fine-tuned regulatory network system between these two proteins. Future work aims to characterize putative regulators and effectors of sirtuin- and FOXO-related pathways using molecular approaches such and RNA interference knockdown of individual FOXO-isoforms. Inter-connectivity of the pathways will provide invaluable insight into current understanding of cell degeneration diseases such as diabetes, cancers and neurological disorders. Keywords: Serial concentration experiment
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Project description:Experiment type: Expression profiling by microarray and RNA-seq data, Third-party re-analysis The purpose of our study is to construct breast cancer cell line BT20-specific interactome by aggregating publically available microarray or RNA-seq samples, and identify novel transcriptional regulators that control breast cancer progression. We collected 101 samples of BT20 cell line microarray or RNA-seq from 12 prior studies and our own study data, GSE120919. We performed normalization for Affymetrix microarray platform and Illumina HiSeq and NovaSeq platform datasets. For the normalization, we used SCAN.UPC R package (ver.2.24.0, PMID: 22959562, https://www.bioconductor.org/packages/release/bioc/html/SCAN.UPC.html) on Affymetrix microarray platform datasets. We use Rsubread R package (ver.1.30.5, PMID: 23558742, http://bioconductor.org/packages/Rsubread/), TPM log2 values on Illumina HiSeq and NovaSeq platform datasets. And then, we performed batch effect adjusting to combine the datasets which came from different laboratories. The matrix data we deposited in GEO has normalized log2 signal intensity for 12,360 genes, and the genes were mapped to human Entrez Gene IDs that overlapped across 13 datasets (a total number of 101 samples). BT20-specific interactome was assembled by Algorithm for the Reconstruction of Accurate Cellular Networks (ARACNe, PMID: 16723010). Then, we used Master Regulator Analysis-Fisher?s Extact Test (MRA-FET, PMID: 20531406) to infer transcription factors which control a gene signature dysregulated by a fusion gene in BT20 cell line (please refer to GSE120919). We discovered SNAI2 as a master regulator candidate to modulate the gene signature in the fusion gene expressing BT20. Our findings will provide biological insights into the role of the fusion gene in breast cancer.
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