The mouse DNA methyltransferase 5'-region. A unique housekeeping gene promoter.

Rouleau, J.; Tanigawa, G; Szyf, Moshe

doi:10.1016/s0021-9258(18)42526-4

Cited by 75 publications

(4 citation statements)

References 53 publications

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“…Interestingly, DNA MeTase is a housekeeping gene without 5Ј CpG island and, thus, its expression is insensitive to NO (see above). In contrast, it has a specific promoter containing activating protein (AP)-1, AP-2, and glucocorticoid response elements (53), suggesting a potentially high level of regulation by cellular signal transduction pathways.…”

Section: Resultsmentioning

confidence: 99%

Methylation-Dependent Gene Silencing Induced by Interleukin 1β via Nitric Oxide Production

Hmadcha

Bedoya

Sobrino

et al. 1999

The Journal of Experimental Medicine

196

134

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Interleukin (IL)-1β is a pleiotropic cytokine implicated in a variety of activities, including damage of insulin-producing cells, brain injury, or neuromodulatory responses. Many of these effects are mediated by nitric oxide (NO) produced by the induction of NO synthase (iNOS) expression. We report here that IL-1β provokes a marked repression of genes, such as fragile X mental retardation 1 (FMR1) and hypoxanthine phosphoribosyltransferase (HPRT), having a CpG island in their promoter region. This effect can be fully prevented by iNOS inhibitors and is dependent on DNA methylation. NO donors also cause FMR1 and HPRT gene silencing. NO-induced methylation of FMR1 CpG island can be reverted by demethylating agents which, in turn, produce the recovery of gene expression. The effects of IL-1β and NO appear to be exerted through activation of DNA methyltransferase (DNA MeTase). Although exposure of the cells to NO does not increase DNA MeTase gene expression, the activity of the enzyme selectively increases when NO is applied directly on a nuclear protein extract. These findings reveal a previously unknown effect of IL-1β and NO on gene expression, and demonstrate a novel pathway for gene silencing based on activation of DNA MeTase by NO and acute modification of CpG island methylation.

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Section: Resultsmentioning

confidence: 99%

Methylation-Dependent Gene Silencing Induced by Interleukin 1β via Nitric Oxide Production

Hmadcha

Bedoya

Sobrino

et al. 1999

The Journal of Experimental Medicine

196

134

View full text Add to dashboard Cite

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“…Transfections were performed using calcium phosphate precipitation as described previously) [51]. Cells were harvested 48 h after transfection and luciferase activity was assayed using the Luciferase Assay System (Promega).…”

Section: Methodsmentioning

confidence: 99%

DNA Methylation of SPARC and Chronic Low Back Pain

et al. 2011

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BackgroundThe extracellular matrix protein SPARC (Secreted Protein, Acidic, Rich in Cysteine) has been linked to degeneration of the intervertebral discs and chronic low back pain (LBP). In humans, SPARC protein expression is decreased as a function of age and disc degeneration. In mice, inactivation of the SPARC gene results in the development of accelerated age-dependent disc degeneration concurrent with age-dependent behavioral signs of chronic LBP.DNA methylation is the covalent modification of DNA by addition of methyl moieties to cytosines in DNA. DNA methylation plays an important role in programming of gene expression, including in the dynamic regulation of changes in gene expression in response to aging and environmental signals.We tested the hypothesis that DNA methylation down-regulates SPARC expression in chronic LBP in pre-clinical models and in patients with chronic LBP.ResultsOur data shows that aging mice develop anatomical and behavioral signs of disc degeneration and back pain, decreased SPARC expression and increased methylation of the SPARC promoter. In parallel, we show that human subjects with back pain exhibit signs of disc degeneration and increased methylation of the SPARC promoter. Methylation of either the human or mouse SPARC promoter silences its activity in transient transfection assays.ConclusionsThis study provides the first evidence that DNA methylation of a single gene plays a role in chronic pain in humans and animal models. This has important implications for understanding the mechanisms involved in chronic pain and for pain therapy.

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“…2B). These genes are generally considered as housekeeping genes, as they are activated in most tissues or growth conditions (Rouleau, et al 1992; Butte, et al 2001). In contrast, genes with long 5′ UTR are significantly enriched in those encoding transcription factors or kinase (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

The evolution of 5'UTR length was shaped by natural selection for its functional impact on gene expression

Zhan,

Hu,

et al. 2024

Preprint

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The 5'UTR of mRNA transcripts differs in length by three orders of magnitude among genes within a eukaryotic genome. Many genes also generate transcript isoforms with heterogeneous lengths of 5'UTR by transcription from distantly located transcription start sites (TSSs). A null model was proposed that the diversification of 5'UTR length is largely stochastic attributing to random gain or loss of TSS and 5'UTR length evolved neutrally by genetic drift ("the null model"). Yet, multiple studies reported observations that are inconsistent with the null model. We conducted integrative analyses of multi-omics data to revisit the functional significance and evolution of 5'UTR length. Our results reveal a strong negative correlation between transcripts' 5'UTR lengths and their expression levels. Regulatory and evolutionary changes of 5'UTR lengths are also negatively associated with changes in expression levels. We proposed that the fixation of a 5'UTR length variant has been shaped by nature selection to better meet different expression demands among genes due to a negative impact of long 5'UTR on translation efficiency. As the expression demands are highly diverse among genes and dynamic in response to environmental changes, different lengths of 5'UTR were favored by natural selection during evolution, creating a highly diverse landscape of 5'UTR lengths. Our model improves understanding of the evolution of gene structure in eukaryotes, and supports that ATU might facilitate fine-tuning of gene expression outcome by producing different lengths of 5'UTR to adjust translation efficiency.

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The mouse DNA methyltransferase 5'-region. A unique housekeeping gene promoter.

Cited by 75 publications

References 53 publications

Methylation-Dependent Gene Silencing Induced by Interleukin 1β via Nitric Oxide Production

Methylation-Dependent Gene Silencing Induced by Interleukin 1β via Nitric Oxide Production

DNA Methylation of SPARC and Chronic Low Back Pain

The evolution of 5'UTR length was shaped by natural selection for its functional impact on gene expression

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