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Project description:miR-29 controls aging-related phenotypes through regulation of the p53 signaling pathway
| PRJNA421320 | ENA
Project description:Aging is a multifactorial process that affects most of the biological functions of the organism and increases susceptibility to disease and death. Recent studies with animal models of accelerated aging have unveiled some mechanisms that also operate in physiological aging. However, little is known about the role of microRNAs (miRNAs) in this process. To address this question, we have analysed miRNA levels in Zmpste24-deficient mice, a model of Hutchinson-Gilford progeria syndrome. We have found that expression of the miR-29 family of miRNAs is markedly upregulated in Zmpste24(-/-) progeroid mice as well as during normal aging in mouse. Functional analysis revealed that this transcriptional activation of miR-29 is triggered in response to DNA damage and occurs in a p53-dependent manner since p53(-/-) murine fibroblasts do not increase miR-29 expression upon doxorubicin treatment. We have also found that miR-29 represses Ppm1d phosphatase, which in turn enhances p53 activity. Based on these results, we propose the existence of a novel regulatory circuitry involving miR-29, Ppm1d and p53, which is activated in aging and in response to DNA damage.
| S-EPMC3117645 | biostudies-literature
Project description:Crohn's disease (CD) is a chronic inflammatory gut disorder. Molecular mechanisms underlying the clinical heterogeneity of CD remain poorly understood. MicroRNAs (miRNAs) are important regulators of gut physiology and several have been implicated in the pathogenesis of adult CD. However, there is a dearth of large-scale miRNA studies for pediatric CD. We hypothesized that specific miRNAs uniquely mark pediatric CD. We performed small RNA-sequencing of patient-matched non-inflamed colon and ileum biopsies from treatment-naïve pediatric patients with CD (n=169) and a control cohort (n=108). Comprehensive miRNA analysis revealed 58 miRNAs altered in pediatric CD. Notably, multinomial logistic regression analysis revealed that index levels of ileal miR-29 are strongly predictive of severe inflammation and stricturing. Transcriptomic analyses of transgenic mice overexpressing miR-29 show a significant reduction of the tight junction protein gene Pmp22 and classic Paneth cell markers. The dramatic loss of Paneth cells was confirmed by histologic assays. Moreover, we also found that pediatric CD patients with elevated miR-29 exhibit significantly lower Paneth cell counts, increased inflammation scores, and reduced levels of PMP22. These findings strongly indicate that miR-29 up-regulation is a distinguishing feature of pediatric CD, highly predictive of severe phenotypes, and associated with inflammation and Paneth cell loss.
2022-12-23 | GSE221261 | GEO
Project description:MicroRNAs (miRs) control the expression of diverse subsets of target mRNAs, and studies have found miR dysregulation in failing hearts. Expression of miR-29 is abundant in heart, increased with aging, and altered in cardiomyopathies. Prior studies demonstrate that miR-29 reduction via genetic knockout or pharmacologic blockade can blunt cardiac hypertrophy and fibrosis in mice. Surprisingly, this depended on specifically blunting miR-29 actions in cardiomyocytes versus fibroblasts. To begin developing more translationally-relevant vectors, we generated a novel transgene-encoded miR-29 inhibitor (TuD-29) that can be incorporated into a viral-mediated gene therapy for cardioprotection. Herein, we corroborate that miR-29 expression and activity is higher in cardiomyocytes versus fibroblasts and demonstrate that TuD-29 effectively blunts hypertrophic responses in cultured cardiomyocytes and mouse hearts. Furthermore, we found that adeno-associated viral (AAV)-mediated miR-29 overexpression in mouse hearts induces early diastolic dysfunction, whereas AAV:TuD-29 treatment improves cardiac output by increasing end-diastolic and stroke volumes. Integration of RNA-seq and miR-target interactomes reveals that miR-29 regulates genes involved in calcium handling, cell stress and hypertrophy, metabolism, ion transport, and extracellular matrix remodeling. These investigations support a likely versatile role for miR-29 in influencing myocardial compliance and relaxation, potentially providing a unique therapeutic avenue to improve diastolic function in heart failure patients.
2023-11-21 | GSE241423 | GEO
Project description:Neonates are highly susceptible to repeat infection and respond poorly to vaccination; these attributes derive from intrinsic differences between neonatal and adult naïve CD8+ T cells. In contrast to adult cells, naïve neonatal cells exhibit a greatly limited ability to differentiate into memory cells, a fundamental property of their adult counterparts. Here, we describe the role of the miR-29 microRNA in naïve T cells, focusing on age-related differences in miR-29 expression and the consequences of these differences in adult and neonatal cells, from mice and humans. In adults, high expression of miR-29 licenses naïve cells towards eventual memory cell fates; whereas neonatal naïve cells, which lack high expression of miR-29, are predisposed towards effector cell fates in response to an infection. Multiple lines of evidence support this model, including analysis of a mouse model deficient in miR-29, which we examine with adoptive transfer experiments to define the functional consequences of reduction of miR-29, together with genomic assays to define the regulatory impact of miR-29. Adult miR 29 deficient naïve CD8+ T cells cell are primed for activation and therefore secrete elevated levels of cytolytic molecules, and express transcription factors at levels associated with effector cell differentiation; moreover, these cells exhibit an altered CD8+ T cell memory repertoire, akin to that of neonatal CD8+ T cells. Importantly, we use a method that exploits extracellular vesicles as a delivery vehicle with which to modulate levels of miR-29 in neonatal and adult naïve T cells, examining both human and mouse cells. For example, increasing miR 29 expression in mouse naïve neonatal CD8+ T cells significantly improved the memory response during infection, concomitant with alterations to the chromatin landscape characteristic of cells primed for memory differentiation. Delivery of miR-29 antagomirs to human adult naïve CD8+ T cells was sufficient to induce the adult cells to adopt phenotypes and gene expression signatures normally found in cells present in newborns. This study establishes miR-29 as a key conserved regulator in naïve CD8+ T cells, and by adjusting levels of miR-29, has the potential to underlie therapeutic strategies for controlling the balance of effector versus memory fates in human T cells.
2021-11-08 | GSE159686 | GEO
Project description:Neonates are highly susceptible to repeat infection and respond poorly to vaccination; these attributes derive from intrinsic differences between neonatal and adult naïve CD8+ T cells. In contrast to adult cells, naïve neonatal cells exhibit a greatly limited ability to differentiate into memory cells, a fundamental property of their adult counterparts. Here, we describe the role of the miR-29 microRNA in naïve T cells, focusing on age-related differences in miR-29 expression and the consequences of these differences in adult and neonatal cells, from mice and humans. In adults, high expression of miR-29 licenses naïve cells towards eventual memory cell fates; whereas neonatal naïve cells, which lack high expression of miR-29, are predisposed towards effector cell fates in response to an infection. Multiple lines of evidence support this model, including analysis of a mouse model deficient in miR-29, which we examine with adoptive transfer experiments to define the functional consequences of reduction of miR-29, together with genomic assays to define the regulatory impact of miR-29. Adult miR 29 deficient naïve CD8+ T cells cell are primed for activation and therefore secrete elevated levels of cytolytic molecules, and express transcription factors at levels associated with effector cell differentiation; moreover, these cells exhibit an altered CD8+ T cell memory repertoire, akin to that of neonatal CD8+ T cells. Importantly, we use a method that exploits extracellular vesicles as a delivery vehicle with which to modulate levels of miR-29 in neonatal and adult naïve T cells, examining both human and mouse cells. For example, increasing miR 29 expression in mouse naïve neonatal CD8+ T cells significantly improved the memory response during infection, concomitant with alterations to the chromatin landscape characteristic of cells primed for memory differentiation. Delivery of miR-29 antagomirs to human adult naïve CD8+ T cells was sufficient to induce the adult cells to adopt phenotypes and gene expression signatures normally found in cells present in newborns. This study establishes miR-29 as a key conserved regulator in naïve CD8+ T cells, and by adjusting levels of miR-29, has the potential to underlie therapeutic strategies for controlling the balance of effector versus memory fates in human T cells.
2021-11-08 | GSE159685 | GEO
Project description:Neonates are highly susceptible to repeat infection and respond poorly to vaccination; these attributes derive from intrinsic differences between neonatal and adult naïve CD8+ T cells. In contrast to adult cells, naïve neonatal cells exhibit a greatly limited ability to differentiate into memory cells, a fundamental property of their adult counterparts. Here, we describe the role of the miR-29 microRNA in naïve T cells, focusing on age-related differences in miR-29 expression and the consequences of these differences in adult and neonatal cells, from mice and humans. In adults, high expression of miR-29 licenses naïve cells towards eventual memory cell fates; whereas neonatal naïve cells, which lack high expression of miR-29, are predisposed towards effector cell fates in response to an infection. Multiple lines of evidence support this model, including analysis of a mouse model deficient in miR-29, which we examine with adoptive transfer experiments to define the functional consequences of reduction of miR-29, together with genomic assays to define the regulatory impact of miR-29. Adult miR 29 deficient naïve CD8+ T cells cell are primed for activation and therefore secrete elevated levels of cytolytic molecules, and express transcription factors at levels associated with effector cell differentiation; moreover, these cells exhibit an altered CD8+ T cell memory repertoire, akin to that of neonatal CD8+ T cells. Importantly, we use a method that exploits extracellular vesicles as a delivery vehicle with which to modulate levels of miR-29 in neonatal and adult naïve T cells, examining both human and mouse cells. For example, increasing miR 29 expression in mouse naïve neonatal CD8+ T cells significantly improved the memory response during infection, concomitant with alterations to the chromatin landscape characteristic of cells primed for memory differentiation. Delivery of miR-29 antagomirs to human adult naïve CD8+ T cells was sufficient to induce the adult cells to adopt phenotypes and gene expression signatures normally found in cells present in newborns. This study establishes miR-29 as a key conserved regulator in naïve CD8+ T cells, and by adjusting levels of miR-29, has the potential to underlie therapeutic strategies for controlling the balance of effector versus memory fates in human T cells.
2021-11-08 | GSE159687 | GEO
Project description:Neonates are highly susceptible to repeat infection and respond poorly to vaccination; these attributes derive from intrinsic differences between neonatal and adult naïve CD8+ T cells. In contrast to adult cells, naïve neonatal cells exhibit a greatly limited ability to differentiate into memory cells, a fundamental property of their adult counterparts. Here, we describe the role of the miR-29 microRNA in naïve T cells, focusing on age-related differences in miR-29 expression and the consequences of these differences in adult and neonatal cells, from mice and humans. In adults, high expression of miR-29 licenses naïve cells towards eventual memory cell fates; whereas neonatal naïve cells, which lack high expression of miR-29, are predisposed towards effector cell fates in response to an infection. Multiple lines of evidence support this model, including analysis of a mouse model deficient in miR-29, which we examine with adoptive transfer experiments to define the functional consequences of reduction of miR-29, together with genomic assays to define the regulatory impact of miR-29. Adult miR 29 deficient naïve CD8+ T cells cell are primed for activation and therefore secrete elevated levels of cytolytic molecules, and express transcription factors at levels associated with effector cell differentiation; moreover, these cells exhibit an altered CD8+ T cell memory repertoire, akin to that of neonatal CD8+ T cells. Importantly, we use a method that exploits extracellular vesicles as a delivery vehicle with which to modulate levels of miR-29 in neonatal and adult naïve T cells, examining both human and mouse cells. For example, increasing miR 29 expression in mouse naïve neonatal CD8+ T cells significantly improved the memory response during infection, concomitant with alterations to the chromatin landscape characteristic of cells primed for memory differentiation. Delivery of miR-29 antagomirs to human adult naïve CD8+ T cells was sufficient to induce the adult cells to adopt phenotypes and gene expression signatures normally found in cells present in newborns. This study establishes miR-29 as a key conserved regulator in naïve CD8+ T cells, and by adjusting levels of miR-29, has the potential to underlie therapeutic strategies for controlling the balance of effector versus memory fates in human T cells.
2021-11-08 | GSE159684 | GEO
Project description:Investigation of the effect of miR-29 on de novo lipogenesis.
2019-08-09 | GSE129539 | GEO
Project description:BACKGROUND:A widespread modulation of gene expression occurs in the aging brain, but little is known as to the upstream drivers of these changes. MicroRNAs emerged as fine regulators of gene expression in many biological contexts and they are modulated by age. MicroRNAs may therefore be part of the upstream drivers of the global gene expression modulation correlated with aging and aging-related phenotypes. RESULTS:Here, we show that microRNA-29 (miR-29) is induced during aging in short-lived turquoise killifish brain and genetic antagonism of its function induces a gene-expression signature typical of aging. Mechanicistically, we identified Ireb2 (a master gene for intracellular iron delivery that encodes for IRP2 protein), as a novel miR-29 target. MiR-29 is induced by iron loading and, in turn, it?? reduces IRP2 expression in vivo, therefore limiting intracellular iron delivery in neurons. Genetically modified fish with neuro-specific miR-29 deficiency exhibit increased levels of IRP2 and transferrin receptor, increased iron content, and oxidative stress. CONCLUSIONS:Our results demonstrate that age-dependent miR-29 upregulation is an adaptive mechanism that counteracts the expression of some aging-related phenotypes and its anti-aging activity is primarily exerted by regulating intracellular iron homeostasis limiting excessive iron-exposure in neurons.
| S-EPMC5304403 | biostudies-literature