Effect of Decitabine on SKM-1 and MDS-L Gene Expression
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE164744 | GEO | 2021/01/26
REPOSITORIES: GEO
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Project description:SKM-1 cells were cultured for 28 days in the absence or presence of low doses of the DNMT1 inhibitors DAC (10 nM) or AZA (100 nM). The experiment was carried in two independent set at different times, and with 2 replicates for each condition (Ctl, AZA, DAC) for a total of 12 samples. The SKM-1 cell line is derived from secondary AML arising from MDS, and is one the few representative in vitro models of MDS.
2013-12-11 | E-MTAB-2130 | biostudies-arrayexpress
Project description:To further investigate the action mechanisms of decitabine (DAC), the molecular pathways regulated by DAC were explored using the gene expression profile of MDS-L cells treated with 4 nM DAC or DMSO for 7 days. Genes whose expression changed by more than 2.0-fold following drug treatment were defined as regulated genes. 956 genes were up-regulated and 461 genes down-regulated in MDS-L cells treated with DAC (4 nM) as compared with the control. Gene expression profiling suggested that DAC significantly affects various gene biogroups, including cellular movement, inflammatory response, hematological system development and function, hematopoiesis, and cell death. Decitabine-induced gene expression in MDS-L cells was measured after 7 days exposure at dose of 4 nM. Three independent samples.
2012-09-01 | E-GEOD-39628 | biostudies-arrayexpress
Project description:Mutations in the U2 small nuclear RNA auxiliary factor 1 (U2AF1) gene are the common feature of a major subset in myelodysplastic syndromes (MDS). However, the genetic landscape and molecular pathogenesis of oncogenic U2AF1 S34F mutation in MDS are not totally understood. To understand how the cancer-associated U2AF1 S34F mutation promotes MDS, we next compared independent RNA samples of SKM-1 cells expressing wild-type U2AF1 and S34F mutant U2AF1 using RNA-sequencing (RNA-seq).Differentially expressed genes (DEGs) and significantly enriched pathways were identified by RNA-seq.
2021-03-13 | GSE166798 | GEO
Project description:To further investigate the action mechanisms of decitabine (DAC), the molecular pathways regulated by DAC were explored using the gene expression profile of MDS-L cells treated with 4 nM DAC or DMSO for 7 days. Genes whose expression changed by more than 2.0-fold following drug treatment were defined as regulated genes. 956 genes were up-regulated and 461 genes down-regulated in MDS-L cells treated with DAC (4 nM) as compared with the control. Gene expression profiling suggested that DAC significantly affects various gene biogroups, including cellular movement, inflammatory response, hematological system development and function, hematopoiesis, and cell death.
2012-09-01 | GSE39628 | GEO
Project description:Effect of Decitabine on SKM-1 and MDS-L Gene Expression
| PRJNA691877 | ENA
Project description:We analyzed the functional role of DOR (Diabetes and Obesity Regulated gene) (also named Tp53inp2) in skeletal muscle. We show that DOR has a direct impact on skeletal muscle mass in vivo. Thus, using different transgenic mouse models, we demonstrate that while muscle-specific DOR gain-of-function results in reduced muscle mass, loss-of-function causes muscle hypertrophy. DOR has been described as a protein with two different functions, i.e., a nuclear coactivator and an autophagy regulator (Baumgartner et. al., PLoS One, 2007; Francis et. al., Curr Biol, 2010; Mauvezin et. al., EMBO Rep, 2010; Nowak et. al., Mol Biol Cell, 2009). This is why we decided to analyze which of these two functions could explain the phenotype observed in our mice models. In this regard, we performed a transcriptomic analysis using microarrays looking for genes differentially expressed in the quadriceps muscle of WT and SKM-Tg mice as well as in C and SKM-KO animals. Surprisingly, only a reduced number of genes were dysregulated upon DOR manipulation and most of the genes underwent mild changes in expression. These data strongly suggest that DOR does not operate as a nuclear co-factor in mouse skeletal muscle under the conditions subjected to study. In contrast, DOR enhances basal autophagy in skeletal muscle and promotes muscle wasting when autophagy is a contributor to muscle loss. To determine the functional role of DOR in skeletal muscle, we generated transgenic mice (SKM-Tg) overexpressing DOR specifically in skeletal muscle under the Myosin-Light Chain 1 promoter/enhancer. The open reading frame of DOR was introduced in an EcoRI site in the MDAF2 vector, which contains a 1.5 kb fragment of the MLC1 promoter and 0.9 kb fragment of the MLC1/3 gene containing a 3' muscle enhancer element (Rosenthal et. al., PNAS, 1989; Otaegui et. al., FASEB J, 2003). The fragment obtained after the digestion of this construct with BssHII was the one used to generate both transgenic mouse lines. Nontransgenic littermates were used as controls for the transgenic animals (Wt). In addition, a muscle-specific DOR knock-out mouse line (SKM-KO) was also generated by crossing homozygous DOR loxP/loxP mice with a mouse strain expressing Cre recombinase under the control of the Myosin-Light Chain 1 promoter (Bothe et. al., Genesis, 2000). Deletion of exons 3 and 4 driven by Cre recombinase caused the ablation of DOR expression. Non-expressing Cre DOR loxP/loxP littermates were used as controls for knockout animals (C). Four-month-old male mice were used in all experiments. Mice were in a C57BL/6J pure genetic background. We used microarrays to analyze the effect of DOR gain-of-function and DOR ablation on skeletal muscle gene expression Total RNA from quadriceps muscles from 4-month-old male mice was extracted and used for hibridization on Affimetrix microarrays
2014-02-13 | E-GEOD-54917 | biostudies-arrayexpress
Project description:We analyzed the functional role of DOR (Diabetes and Obesity Regulated gene) (also named Tp53inp2) in skeletal muscle. We show that DOR has a direct impact on skeletal muscle mass in vivo. Thus, using different transgenic mouse models, we demonstrate that while muscle-specific DOR gain-of-function results in reduced muscle mass, loss-of-function causes muscle hypertrophy. DOR has been described as a protein with two different functions, i.e., a nuclear coactivator and an autophagy regulator (Baumgartner et. al., PLoS One, 2007; Francis et. al., Curr Biol, 2010; Mauvezin et. al., EMBO Rep, 2010; Nowak et. al., Mol Biol Cell, 2009). This is why we decided to analyze which of these two functions could explain the phenotype observed in our mice models. In this regard, we performed a transcriptomic analysis using microarrays looking for genes differentially expressed in the quadriceps muscle of WT and SKM-Tg mice as well as in C and SKM-KO animals. Surprisingly, only a reduced number of genes were dysregulated upon DOR manipulation and most of the genes underwent mild changes in expression. These data strongly suggest that DOR does not operate as a nuclear co-factor in mouse skeletal muscle under the conditions subjected to study. In contrast, DOR enhances basal autophagy in skeletal muscle and promotes muscle wasting when autophagy is a contributor to muscle loss. To determine the functional role of DOR in skeletal muscle, we generated transgenic mice (SKM-Tg) overexpressing DOR specifically in skeletal muscle under the Myosin-Light Chain 1 promoter/enhancer. The open reading frame of DOR was introduced in an EcoRI site in the MDAF2 vector, which contains a 1.5 kb fragment of the MLC1 promoter and 0.9 kb fragment of the MLC1/3 gene containing a 3' muscle enhancer element (Rosenthal et. al., PNAS, 1989; Otaegui et. al., FASEB J, 2003). The fragment obtained after the digestion of this construct with BssHII was the one used to generate both transgenic mouse lines. Nontransgenic littermates were used as controls for the transgenic animals (Wt). In addition, a muscle-specific DOR knock-out mouse line (SKM-KO) was also generated by crossing homozygous DOR loxP/loxP mice with a mouse strain expressing Cre recombinase under the control of the Myosin-Light Chain 1 promoter (Bothe et. al., Genesis, 2000). Deletion of exons 3 and 4 driven by Cre recombinase caused the ablation of DOR expression. Non-expressing Cre DOR loxP/loxP littermates were used as controls for knockout animals (C). Four-month-old male mice were used in all experiments. Mice were in a C57BL/6J pure genetic background.
2014-02-13 | GSE54917 | GEO
Project description:Azacitidine (AZA) and decitabine (DAC) are cytidine azanucleoside analogs with clinical activity in myelodysplastic syndromes (MDS) and potential activity in solid tumors. To better understand the mechanism of action of these drugs, we examined the effects of AZA and DAC in a panel of non-small cell lung cancer (NSCLC) cell lines. Of 5 NSCLC lines tested in a cell viability assay, all were sensitive to AZA (EC50 of 1.8M-bM-^@M-^S10.5 M-BM-5M), while only H1299 cells were equally sensitive to DAC (EC50 of 5.1 M-BM-5M). In the relatively DAC-insensitive cell line A549, both AZA and DAC caused DNA methyltransferase I depletion and DNA hypomethylation; however, only AZA significantly induced markers of DNA damage and apoptosis, suggesting that mechanisms in addition to, or other than, DNA hypomethylation are important for AZA-induced cell death. Cell cycle analysis indicated that AZA induced an accumulation of cells in sub-G1 phase, whereas DAC mainly caused an increase of cells in G2/M. Gene expression analysis of AZA- and DAC-treated cells revealed strikingly different profiles, with many genes distinctly regulated by each drug. In summary, while both AZA and DAC caused DNA hypomethylation, distinct effects were demonstrated on regulation of gene expression, cell cycle, DNA damage, and apoptosis. A549 and H1299 cells were treated with a dose range (0.3M-bM-^@M-^S3.0 M-NM-<M) of AZA or DAC for 48 hours, and effects on gene expression were assessed by microarray analysis.
2011-05-05 | E-GEOD-29077 | biostudies-arrayexpress
Project description:Azacitidine (AZA) and decitabine (DAC) are cytidine azanucleoside analogs with clinical activity in myelodysplastic syndromes (MDS) and potential activity in solid tumors. To better understand the mechanism of action of these drugs, we examined the effects of AZA and DAC in a panel of non-small cell lung cancer (NSCLC) cell lines. Of 5 NSCLC lines tested in a cell viability assay, all were sensitive to AZA (EC50 of 1.8–10.5 µM), while only H1299 cells were equally sensitive to DAC (EC50 of 5.1 µM). In the relatively DAC-insensitive cell line A549, both AZA and DAC caused DNA methyltransferase I depletion and DNA hypomethylation; however, only AZA significantly induced markers of DNA damage and apoptosis, suggesting that mechanisms in addition to, or other than, DNA hypomethylation are important for AZA-induced cell death. Cell cycle analysis indicated that AZA induced an accumulation of cells in sub-G1 phase, whereas DAC mainly caused an increase of cells in G2/M. Gene expression analysis of AZA- and DAC-treated cells revealed strikingly different profiles, with many genes distinctly regulated by each drug. In summary, while both AZA and DAC caused DNA hypomethylation, distinct effects were demonstrated on regulation of gene expression, cell cycle, DNA damage, and apoptosis.
2011-05-05 | GSE29077 | GEO
Project description:Myelodysplastic syndromes (MDS) are a group of clonal myeloid neoplasms characterized by ineffective hematopoiesis and cytopenia. Hypomethylating agents (HMAs) play a central role in the treatment of high-risk MDS, but their mechanisms of action are diverse and not fully understood. To investigate the molecular mechanisms of HMA, an MDS cell line (MDS-L) was cultured with a non-toxic concentration of decitabine for 6 months and drug sensitivity, cell differentiation, and DNA methylation profiles were evaluated. Cells with long-term exposure to decitabine (MDS-L-DAC) were morphologically mature with nuclear lobulation and cytoplasmic granulation, accompanied by decreased expression of the CD34 surface antigen. MDS-L-DAC cells exhibited decreased WT1 expression and intense induction of apoptosis by DAC. DNA methylation array analysis revealed the demethylation of the membrane spanning 4-domains A3 (MS4A3) genes and microRNA-143 (MIR143) in MDS-L-DAC cells. MIR143 functions as a tumor suppressor through the MAPK/ERK pathway, and in MDS-L-DAC cells, decreased expression of KRAS and β-catenin was observed in response to the increased expression of MIR143. The differentiation of MDS cells and decreased expression of WT1 induced by long-term incubation with DAC may involve the restoration of function via demethylation of the MIR143 and MS4A3 gene promoters, which may contribute to eliminating the malignant phenotype through reductions in KRAS and β-catenin expression.
2025-04-06 | GSE293053 | GEO