Estrogen-driven control of diabetogenic gene networks is associated with reduced levels of miR-224/452 circulating in extracellular vesicles
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ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE147966 | GEO | 2020/12/01
REPOSITORIES: GEO
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Project description:Women with diabetes have a higher prevalence of cardiovascular complications than men, suggesting that sex-steroid hormones like estrogen may impact on female health in diabetes. Here we demonstrate that estrogen suppletion and insulin resistance in male-to-female transgenders coincides with lower plasma levels of miR-224 and miR-452 carried in extracellular vesicles. Systemic silencing of miR-224 and miR-452 in mice triggered a prediabetic phenotype with higher plasma insulin levels, increased white adipose lipogenesis and less glucose uptake and mitochondrial respiration in brown adipose tissue. Consistent with a prediabetic metabolic state, RNA sequencing demonstrated differential expression of genes involved in lipogenesis in white adipose tissue and mitochondrial respiration and glucose uptake in brown adipose tissue. In vitro studies confirmed the estrogen-dependent lowering of miR-224 (brown adipocytes) and miR-452 (white adipocytes) and their impact on adipocyte-specific metabolic processes. Collectively, we identified novel estrogen-driven, post-transcriptional networks that could drive the progression to insulin resistance in transwomen and provide potential anti-diabetic therapeutic targets in women.
2020-12-01 | GSE147965 | GEO
Project description:Women with diabetes have a higher prevalence of cardiovascular complications than men, suggesting that sex-steroid hormones like estrogen may impact on female health in diabetes. Here we demonstrate that estrogen suppletion and insulin resistance in male-to-female transgenders coincides with lower plasma levels of miR-224 and miR-452 carried in extracellular vesicles. Systemic silencing of miR-224 and miR-452 in mice triggered a prediabetic phenotype with higher plasma insulin levels, increased white adipose lipogenesis and less glucose uptake and mitochondrial respiration in brown adipose tissue. Consistent with a prediabetic metabolic state, RNA sequencing demonstrated differential expression of genes involved in lipogenesis in white adipose tissue and mitochondrial respiration and glucose uptake in brown adipose tissue. In vitro studies confirmed the estrogen-dependent lowering of miR-224 (brown adipocytes) and miR-452 (white adipocytes) and their impact on adipocyte-specific metabolic processes. Collectively, we identified novel estrogen-driven, post-transcriptional networks that could drive the progression to insulin resistance in transwomen and provide potential anti-diabetic therapeutic targets in women.
2020-12-01 | GSE147872 | GEO
Project description:Estrogen-driven control of diabetogenic gene networks is associated with reduced levels of miR-224/452 circulating in extracellular vesicles
| PRJNA622678 | ENA
Project description:ObjectiveSex steroid hormones like estrogens have a key role in the regulation of energy homeostasis and metabolism. In transwomen, gender-affirming hormone therapy like estradiol (in combination with antiandrogenic compounds) could affect metabolism as well. Given that the underlying pathophysiological mechanisms are not fully understood, this study assessed circulating estradiol-driven microRNAs (miRs) in transwomen and their regulation of genes involved in metabolism in mice.MethodsFollowing plasma miR-sequencing (seq) in a transwomen discovery (n = 20) and validation cohort (n = 30), we identified miR-224 and miR-452. Subsequent systemic silencing of these miRs in male C57Bl/6 J mice (n = 10) was followed by RNA-seq-based gene expression analysis of brown and white adipose tissue in conjunction with mechanistic studies in cultured adipocytes.ResultsEstradiol in transwomen lowered plasma miR-224 and -452 carried in extracellular vesicles (EVs) while their systemic silencing in mice and cultured adipocytes increased lipogenesis (white adipose) but reduced glucose uptake and mitochondrial respiration (brown adipose). In white and brown adipose tissue, differentially expressed (miR target) genes are associated with lipogenesis (white adipose) and mitochondrial respiration and glucose uptake (brown adipose).ConclusionThis study identified an estradiol-drive post-transcriptional network that could potentially offer a mechanistic understanding of metabolism following gender-affirming estradiol therapy.
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Project description:Estrogen-driven control of diabetogenic gene networks is associated with reduced levels of miR-224/452 circulating in extracellular vesicles [RNA-Seq]
| PRJNA622444 | ENA
Project description:Estrogen-driven control of diabetogenic gene networks is associated with reduced levels of miR-224/452 circulating in extracellular vesicles [miRNA-Seq]
| PRJNA622680 | ENA
Project description:Most cancer-related deaths are caused by distant metastases, which are tumour cells that have escaped from a primary tumour and passed into the bloodstream to colonize a new organ. In this context, communication between tumour and stromal cells is essential. Indeed, tumor cells interact with cells in the tumor microenvironment and are able to modify them to their advantage. Both extracellular vesicles (EVs) and exosomes are heterogeneous populations of small vesicles present in the tumor microenvironment and in body fluids that have recently emerged as powerful mediators involved in this communication and their transport in fluids. Tumor cells release large quantities of exosomes containing tumor markers, which can then spread to distant locations.
The exosomes are of endosomal origin. They are composed of proteins, lipids, RNA and DNA, and they circulate in the bloodstream. They can be internalized by specific distant cells and thus deliver a functional message. It has recently been shown that tumor exosomes containing pro-metastatic factors form pre-metastatic niches, before the tumor cells actually arrive, while determining the metastatic organotropism of tumors. These properties are now opening up new avenues of research in tumor biomarkers. In recent years, several studies have highlighted different markers contained specifically in exosomes derived from cancer cells. Consequently, exosomes are considered as potential reservoirs of tumor biomarkers that could be clinically useful for the non-invasive diagnosis of cancer, with the advantage of being performed by liquid biopsy. The study of microRNA (miRNA) is of particular interest. Indeed, miRNAs are small non-coding RNAs (between 21 and 25 nucleotides) involved in the regulation of gene expression and which are frequently deregulated in cancer. Several studies underline that the variation of free miRNAs in the blood is correlated with the progression of the disease, particularly in colon cancer. However, the stability of free miRNAs is controversial. Therefore, exosomes represent a very advantageous means of transporting miRNAs in the blood, as they are able to protect miRNAs from degradation by RNAase.
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Project description:Malignant melanoma is highly lethal due to its aggressive invasive properties and metastatic dissemination. The transcription factor E2F1 is crucial for melanoma progression through poorly understood mechanisms. Here, we show that the miR-224/miR-452 cluster is significantly increased in advanced melanoma and invasive/metastatic cell lines that express high levels of E2F1. miR-224/miR-452 expression is directly activated by E2F1 through transactivation of the GABRE gene. Ectopic expression of miR-224/miR-452 in less aggressive cells induces EMT and cytoskeletal rearrangements and enhances migration/invasion. Conversely, miR-224/miR-452 depletion in metastatic cells induces the reversal of EMT, inhibition of motility, loss of the invasive phenotype and an absence of lung metastases in mice. We identify the metastasis suppressor TXNIP as new target of miR-224/miR-452 that induces feedback inhibition of E2F1 and show that miR-224/452-mediated downregulation of TXNIP is essential for E2F1-induced EMT and invasion. The E2F1-miR-224/452-TXNIP axis constitutes a molecular signature that predicts patient survival and may help to set novel therapies.
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