Physiological concentration changes of intracellular spermine activates DNA methyltransferase 3A and 3B and affects gene methylation
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PROVIDER: PRJNA438224 | ENA |
REPOSITORIES: ENA
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Project description:Polyamines are essential for various cell functions and are produced in most cells, as well as being taken up from extracellular sources. Polyamines, especially spermine, in blood cells increase when polyamines are supplied from the digestive tract. Altered polyamine metabolism has an impact on substrate concentrations and enzyme activities involved in gene methylation, and may affect gene expression. Therefore, we investigated the effect of decreased polyamine synthesis and extracellular spermine supply on substrate concentrations and enzyme activities involved in gene methylation and on changes of methylation in promoter regions using methylation arrays. In Jurkat cells and human mammary epithelial cells, changes in polyamine concentrations differed after polyamine synthesis inhibition. However, S-adenosylmethionine decarboxylase activity and the decarboxylated S-adenosylmethionine to S-adenosyl-L-methionine ratio were decreased by spermine addition in both cells. After inhibiting polyamine synthesis in Jurkat cells by D,L-alpha-difluoromethylornithine, the protein levels of DNA methyltransferase (DNMT) 1, 3A and 3B were not changed, but the activity of the three enzymes markedly decreased. The protein levels of these enzymes were not changed by addition of spermine; however, DNMT 3B was markedly activated and DNMT 3A was also activated. DNMT 1 was not activated. Effects on methylation of promoter regions included significant changes for tumor suppressor genes in response to altered polyamine metabolism. However, no significant changes in methylation status were found on genes of which methylation status and their related protein levels were affected by spermine. When considering these results, there are many genes for which polyamines have an impact on expression via methylation of promoter regions.
2018-03-15 | GSE111807 | GEO
Project description:Gene expression data from AML cell lines, MOLM-14, U937, THP-1 and HL-60, that were infected with a scrambled control hairpin (shControl), two shRNAs directed against GSK-3B (shGSK3B_1 and shGSK3B_2), or two shRNAs directed against GSK-3A (shGSK3A_5 and shGSK3A_6). Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults. Long-term survival of patients with AML has changed little over the past decade, necessitating the identification and validation of new AML targets. Integration of genomic approaches with small-molecule and genetic-based high-throughput screening holds the promise of improved discovery of candidate targets for cancer therapy. Here, we identified a role for glycogen synthase kinase 3A (GSK-3A) in AML by performing two independent small-molecule library screens and an shRNA screen for perturbations that induced a differentiation expression signature in AML cells. GSK-3 is a serine-threonine kinase involved in diverse cellular processes including differentiation, signal transduction, cell cycle regulation, and proliferation. We demonstrated that specific loss of GSK-3A induced differentiation in AML by multiple measurements, including induction of gene expression signatures, morphological changes, and cell surface markers consistent with myeloid maturation. GSK-3AM-bM-^@M-^Sspecific suppression also led to impaired growth and proliferation in vitro, induction of apoptosis, loss of colony formation in methylcellulose, and anti-AML activity in vivo. Although the role of GSK-3B has been well studied in cancer development, these studies support a role for GSK-3A in AML. The AML cell lines, MOLM-14, U937, THP-1 and HL-60, were infected with a scrambled control hairpin (shControl), two shRNAs directed against GSK-3B (shGSK3B_1 and shGSK3B_2), and two shRNAs directed against GSK-3A (shGSK3A_5 and shGSK3A_6).
2012-02-27 | E-GEOD-35200 | biostudies-arrayexpress
Project description:Gene expression data from AML cell lines, MOLM-14, U937, THP-1 and HL-60, that were infected with a scrambled control hairpin (shControl), two shRNAs directed against GSK-3B (shGSK3B_1 and shGSK3B_2), or two shRNAs directed against GSK-3A (shGSK3A_5 and shGSK3A_6). Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults. Long-term survival of patients with AML has changed little over the past decade, necessitating the identification and validation of new AML targets. Integration of genomic approaches with small-molecule and genetic-based high-throughput screening holds the promise of improved discovery of candidate targets for cancer therapy. Here, we identified a role for glycogen synthase kinase 3A (GSK-3A) in AML by performing two independent small-molecule library screens and an shRNA screen for perturbations that induced a differentiation expression signature in AML cells. GSK-3 is a serine-threonine kinase involved in diverse cellular processes including differentiation, signal transduction, cell cycle regulation, and proliferation. We demonstrated that specific loss of GSK-3A induced differentiation in AML by multiple measurements, including induction of gene expression signatures, morphological changes, and cell surface markers consistent with myeloid maturation. GSK-3A–specific suppression also led to impaired growth and proliferation in vitro, induction of apoptosis, loss of colony formation in methylcellulose, and anti-AML activity in vivo. Although the role of GSK-3B has been well studied in cancer development, these studies support a role for GSK-3A in AML.
2012-02-27 | GSE35200 | GEO
Project description:DNA methyltransferases 3A and 3B target specific sequences during mouse gastrulation
| PRJNA821521 | ENA
Project description:Using an unbiased metabolomics approach and a IFN-stimulated response elements (ISRE) reporter screening system, we have identified the cellular metabolite spermine as an endogenous brake restraining IFN-I signaling and autoinflammation. Cellular spermine concentration decrease upon stimulations with IFN-I, IL-2, and IL-6. Spermine suppresses phosphorylation of JAK1 in macrophages responding to IFN-I, T cells responding to IL-2, and fibroblasts responding to IL-6. Mechanistically, spermine binds directly to the N-terminal domains of JAK1, resulting in impaired IFNAR2-JAK1 interaction required for initiating downstream signaling and, subsequently, restrained IFN-I effector response. Moreover, spermine attenuates SLE progression in an SLE murine model and reduces IFN-I signaling in PBMCs from SLE patients.
2024-06-21 | GSE192366 | GEO
Project description:Targeted disruption of DNMT1, 3A and 3B in human embryonic stem cells
| PRJNA267139 | ENA
Project description:Combining metabolomics analyses with an IFN-stimulated response elements reporter system, we identify spermine as a cellular metabolite brake for JAK1 signaling. Spermine directly binds to FERM and SH2 domains of JAK1 to impair IFNAR2-JAK1 interaction. Spermine suppresses JAK1 phosphorylation triggered by types I and II cytokines, including IFN-I/II, IL-2, and IL-6. Spermine treatment attenuates autoimmune pathogenesis in a SLE murine model and reduces IFN-I signaling in monocytes from SLE patients, which have reduced spermine levels.
2024-06-21 | GSE218731 | GEO
Project description:DNA methylation is a key epigenetic modification involved in regulating gene expression and maintaining genomic integrity. Somatic patterns of DNA methylation are largely static, apart from focal dynamics at gene regulatory elements. To further advance our understanding of the role of DNA methylation in human development and disease, we inactivated all three catalytically active DNA methyltransferases in human embryonic stem cells (ESCs) using CRISPR/Cas9 genome editing. Disruption of DNMT3A or DNMT3B individually, as well as of both enzymes in tandem, creates viable, pluripotent cell lines with distinct effects on their DNA methylation landscape as assessed by whole-genome bisulfite sequencing. Surprisingly, in contrast to mouse, deletion of DNMT1 resulted in rapid cell death in human ESCs. To overcome the immediate lethality, we generated a doxycycline (DOX) responsive tTA-DNMT1* rescue line and readily obtained homozygous DNMT1 mutant lines. However, DOX-mediated repression of the exogenous DNMT1* initiates rapid, global loss of DNA methylation, followed by extensive cell death, demonstrating that DNA methylation is essential for human ESCs cultured in standard conditions. In summary, our data provide a comprehensive characterization of DNMT mutant ESCs, including single base genome-wide maps of their targets. RRBS methylation profiling of DNMT3A/3B DKO human ES cells
2015-03-30 | E-GEOD-63280 | biostudies-arrayexpress
Project description:Combining metabolomics analyses with an IFN-stimulated response elements reporter system, we identify spermine as a cellular metabolite brake for JAK1 signaling. Spermine directly binds to FERM and SH2 domains of JAK1 to impair IFNAR2-JAK1 interaction. Spermine suppresses JAK1 phosphorylation triggered by types I and II cytokines, including IFN-I/II, IL-2, and IL-6. Spermine treatment attenuates autoimmune pathogenesis in a SLE murine model and reduces IFN-I signaling in monocytes from SLE patients, which have reduced spermine levels.
2024-06-21 | GSE222887 | GEO