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Project description:In type 1 diabetes, the appearance of islet autoantibodies indicates the onset of islet autoimmunity, often many years before clinical symptoms arise. While T cells play a major role in the destruction of pancreatic beta cells, molecular underpinnings promoting aberrant T cell activation remain poorly understood. Here, we show that during islet autoimmunity an miR142-3p/Tet2/Foxp3 axis interferes with the efficient induction of regulatory T (Treg) cells, resulting in impaired Treg stability in mouse and human. Specifically, we demonstrate that miR142-3p is induced in islet autoimmunity and that its inhibition enhances Treg induction and stability, leading to reduced islet autoimmunity in non-obese diabetic mice. Using various cellular and molecular approaches we identify Tet2 as a direct target of miR142-3p, thereby linking high miR142-3p levels to epigenetic remodeling in Tregs. These findings offer a mechanistic model where during islet autoimmunity miR142-3p/Tet2-mediated Treg instability contributes to autoimmune activation and progression.
| S-EPMC6910913 | biostudies-literature
Project description:In type 1 diabetes (T1D), the appearance of multiple islet autoantibodies indicates the onset of islet autoimmunity, often many years before clinical symptoms arise. However, the underlying molecular mechanisms in T cells that can promote aberrant activation thereby triggering autoimmune progression remain poorly understood. Here, we show that during early stages of islet autoimmunity a miRNA142-3p/Tet2 signaling axis in murine and human CD4+T cells interferes with the efficient induction of regulatory T (Treg) cells accompanied by impairments in Treg stability. Specifically, we demonstrate that miR142-3p is induced in islet autoimmunity, while its inhibition enhances Treg induction and stability accompanied by a reduction of islet autoimmunity in non-obese diabetic (NOD) mice. Mechanistically, using HITS-CLIP analyses we identify the methylcytosine dioxygenase Tet2 as a direct target of miR142-3p in CD4+T cells, thereby linking high miR142-3p levels to epigenetic remodeling and impairments in Treg induction and stability. These findings offer a new mechanistic model where during islet-autoimmunity miR142-3p/Tet2-mediated Treg instability can contribute to autoimmune activation and progression.
2019-11-14 | GSE124264 | GEO
Project description:In type 1 diabetes (T1D), the appearance of multiple islet autoantibodies indicates the onset of islet autoimmunity, often many years before clinical symptoms arise. However, the underlying molecular mechanisms in T cells that can promote aberrant activation thereby triggering autoimmune progression remain poorly understood. Here, we show that during early stages of islet autoimmunity a miRNA142-3p/Tet2 signaling axis in murine and human CD4+T cells interferes with the efficient induction of regulatory T (Treg) cells accompanied by impairments in Treg stability. Specifically, we demonstrate that miR142-3p is induced in islet autoimmunity, while its inhibition enhances Treg induction and stability accompanied by a reduction of islet autoimmunity in non-obese diabetic (NOD) mice. Mechanistically, using HITS-CLIP analyses we identify the methylcytosine dioxygenase Tet2 as a direct target of miR142-3p in CD4+T cells, thereby linking high miR142-3p levels to epigenetic remodeling and impairments in Treg induction and stability. These findings offer a new mechanistic model where during islet-autoimmunity miR142-3p/Tet2-mediated Treg instability can contribute to autoimmune activation and progression.
2019-11-14 | GSE140064 | GEO
Project description:miRNA142-3p targets Tet2 and impairs Treg differentiation and stability in models of type 1 diabetes
| PRJNA588167 | ENA
Project description:miRNA142-3p targets Tet2 and impairs Treg differentiation and stability in models of type 1 diabetes
| PRJNA511438 | ENA
Project description:miRNA142-3p targets Tet2 and impairs Treg differentiation and stability in models of type 1 diabetes
| PRJNA588161 | ENA
Project description:Foxp3-positive regulatory T cells (Tregs) are crucial for the maintenance of immune homeostasis and keep immune responses in check. Upon activation, Tregs are transferred into an effector state expressing transcripts essential for their suppressive activity, migration, and survival. However, it is not completely understood how different intrinsic and environmental factors control differentiation. Here, we present for the first time to our knowledge data suggesting that Treg-intrinsic expression of CD83 is essential for Treg differentiation upon activation. Interestingly, mice with Treg-intrinsic CD83 deficiency are characterized by a proinflammatory phenotype. Furthermore, the loss of CD83 expression by Tregs leads to the downregulation of Treg-specific differentiation markers and the induction of an inflammatory profile. In addition, Treg-specific conditional knockout mice showed aggravated autoimmunity and an impaired resolution of inflammation. Altogether, our results show that CD83 expression in Tregs is an essential factor for the development and function of effector Tregs upon activation. Since Tregs play a crucial role in the maintenance of immune tolerance and thus prevention of autoimmune disorders, our findings are also clinically relevant.
| S-EPMC6124443 | biostudies-literature
Project description:The Telomeric Repeat-binding Factor 2 (TRF2) is a telomere-capping protein that plays a key role in the maintenance of telomere structure and function. It is highly expressed in different cancer types and it contributes to cancer progression. To date, anti-cancer strategies to target TRF2 remain a challenge. Here, we developed a miRNA-based approach to reduce TRF2 expression. By performing a high-throughput luciferase screening of 54 candidate miRNAs, we identified miR-182-3p as a specific and efficient post-transcriptional regulator of TRF2. Ectopic expression of miR-182-3p drastically reduced TRF2 protein levels in a panel of telomerase- or Alternative Lengthening of Telomeres (ALT)-positive cancer cell lines. Moreover, miR-182-3p induced DNA damage at telomeric and pericentromeric sites, eventually leading to strong apoptosis activation. We also observed that treatment with lipid nanoparticles (LNPs) containing miR-182-3p impaired tumor growth in TNBC models, including Patient-Derived Tumor Xenografts (PDTXs), without affecting mouse survival or tissue function. Finally, LNPs-miR-182-3p were able to cross the blood-brain barrier and reduce intracranial tumors representing a possible therapeutic option for metastatic brain lesions.
| S-SCDT-10_15252-EMMM_202216033 | biostudies-other
Project description:TET2 somatic mutations occur in ∼10% of diffuse large B-cell lymphomas (DLBCL) but are of unknown significance. Herein, we show that TET2 is required for the humoral immune response and is a DLBCL tumor suppressor. TET2 loss of function disrupts transit of B cells through germinal centers (GC), causing GC hyperplasia, impaired class switch recombination, blockade of plasma cell differentiation, and a preneoplastic phenotype. TET2 loss was linked to focal loss of enhancer hydroxymethylation and transcriptional repression of genes that mediate GC exit, such as PRDM1. Notably, these enhancers and genes are also repressed in CREBBP-mutant DLBCLs. Accordingly, TET2 mutation in patients yields a CREBBP-mutant gene-expression signature, CREBBP and TET2 mutations are generally mutually exclusive, and hydroxymethylation loss caused by TET2 deficiency impairs enhancer H3K27 acetylation. Hence, TET2 plays a critical role in the GC reaction, and its loss of function results in lymphomagenesis through failure to activate genes linked to GC exit signals. SIGNIFICANCE: We show that TET2 is required for exit of the GC, B-cell differentiation, and is a tumor suppressor for mature B cells. Loss of TET2 phenocopies CREBBP somatic mutation. These results advocate for sequencing TET2 in patients with lymphoma and for the testing of epigenetic therapies to treat these tumors.See related commentary by Shingleton and Dave, p. 1515.This article is highlighted in the In This Issue feature, p. 1494.
| S-EPMC6279514 | biostudies-literature
Project description:MicroRNAs are known to play a critical role in skeletal myogenesis and maintenance, and cofilin-2 (CFL2) is necessary for actin cytoskeleton dynamics and myogenic differentiation. Nonetheless, target molecules and the modes of action of miRNAs, especially those responsible for the inhibitory mechanism on the myogenesis by saturated fatty acids (SFA) or obesity, still remain unclear. Here, we reported the role played by miR-429-3p on CFL2 expression, actin filament dynamics, myoblast proliferation, and myogenic differentiation in C2C12 cells. Palmitic acid (PA), the most abundant SFA in diet, inhibited the myogenic differentiation of myoblasts, accompanied by CFL2 reduction and miR-429-3p induction. Interestingly, miR-429-3p suppressed the expression of CFL2 by targeting the 3'UTR of CFL2 mRNA directly. Transfection of miR-429-3p mimic in myoblasts increased F-actin formation and augmented nuclear YAP level, thereby promoting cell cycle progression and myoblast proliferation. Moreover, miR-429-3p mimic drastically suppressed the expressions of myogenic factors, such as MyoD, MyoG, and MyHC, and impaired myogenic differentiation of C2C12 cells. Therefore, this study unveiled the crucial role of miR-429-3p in myogenic differentiation through the suppression of CFL2 and provided implications of SFA-induced miRNA in the regulation of actin dynamics and skeletal myogenesis.
| S-EPMC8535884 | biostudies-literature