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Genome organization and chromatin analysis identify transcriptional downregulation of insulin-like growth factor signaling as a hallmark of aging in developing B cells

ABSTRACT: Genome organization and chromatin analysis identify transcriptional downregulation of insulin-like growth factor signaling as a hallmark of aging in developing B cells

PROVIDER: PRJNA431625 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR6512690_1.fastq.gz	Fastqsanger.gz
	SRR6512690_2.fastq.gz	Fastqsanger.gz
	SRR6512700_1.fastq.gz	Fastqsanger.gz
	SRR6512700_2.fastq.gz	Fastqsanger.gz
	SRR6512710.fastq.gz	Fastqsanger.gz

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Genome organization and chromatin analysis identify transcriptional downregulation of insulin-like growth factor signaling as a hallmark of aging in developing B cells

Project description:Background: Ageing is characterised by loss of function of the adaptive immune system, but the underlying causes are poorly understood. To assess the molecular effects of ageing on B cell development, we have profiled gene expression and chromatin features, including histone modifications and chromosome conformation focused on promoter interactions, globally in murine bone marrow pro-B and pre-B cells. Results: Our analysis revealed that the expression levels of most genes are generally preserved in B cell precursors isolated from aged as compared to young mice. Nonetheless, age-specific expression changes are observed at numerous genes and are underpinned by multi-layered alterations in chromatin structure, including chromatin accessibility, histone modifications, long-range promoter interactions and nuclear compartmentalisation. We identified transcriptional downregulation of components of the insulin-like growth factor signalling pathway, in particular downregulation of Irs1 and upregulation of miR/Let-7 expression, as a signature of the aged phenotype. Remarkably, these expression changes are associated with specific alterations in H3K27me3, suggesting that Polycomb-mediated repression plays a role in precursor B cell ageing. Conclusions: Components of the insulin-like growth factor signalling pathways are key targets of epigenetic regulation in ageing in bone marrow B cell precursors.

2018-06-27 | GSE109671 | GEO

Genome organization and chromatin analysis identify transcriptional downregulation of insulin-like growth factor signaling as a hallmark of aging in developing B cells.

Project description:BACKGROUND:Aging is characterized by loss of function of the adaptive immune system, but the underlying causes are poorly understood. To assess the molecular effects of aging on B cell development, we profiled gene expression and chromatin features genome-wide, including histone modifications and chromosome conformation, in bone marrow pro-B and pre-B cells from young and aged mice. RESULTS:Our analysis reveals that the expression levels of most genes are generally preserved in B cell precursors isolated from aged compared with young mice. Nonetheless, age-specific expression changes are observed at numerous genes, including microRNA encoding genes. Importantly, these changes are underpinned by multi-layered alterations in chromatin structure, including chromatin accessibility, histone modifications, long-range promoter interactions, and nuclear compartmentalization. Previous work has shown that differentiation is linked to changes in promoter-regulatory element interactions. We find that aging in B cell precursors is accompanied by rewiring of such interactions. We identify transcriptional downregulation of components of the insulin-like growth factor signaling pathway, in particular downregulation of Irs1 and upregulation of Let-7 microRNA expression, as a signature of the aged phenotype. These changes in expression are associated with specific alterations in H3K27me3 occupancy, suggesting that Polycomb-mediated repression plays a role in precursor B cell aging. CONCLUSIONS:Changes in chromatin and 3D genome organization play an important role in shaping the altered gene expression profile of aged precursor B cells. Components of the insulin-like growth factor signaling pathways are key targets of epigenetic regulation in aging in bone marrow B cell precursors.

| S-EPMC6124017 | biostudies-literature

Human and mouse muscle transcriptomic analyses identify insulin receptor mRNA downregulation in hyperinsulinemia-associated insulin resistance

Project description:Human and mouse muscle transcriptomic analyses identify insulin receptor mRNA downregulation in hyperinsulinemia-associated insulin resistance

| PRJNA614531 | ENA

Human and mouse muscle transcriptomic analyses identify insulin receptor mRNA downregulation in hyperinsulinemia-associated insulin resistance

Project description:Hyperinsulinemia is often viewed as compensatory to insulin resistance, but studies have shown that high levels of insulin may contribute to insulin resistance. The precise mechanisms by which hyperinsulinemia contributes to insulin resistance remain poorly defined. To understand direct effects of prolonged exposure to excess insulin in muscle cells, we incubated differentiated C2C12 myotubes with elevated insulin for 16 hours, followed by 6 hours serum starvation, before examining key insulin signaling nodes. Using this model, we found that prolonged high insulin treatment significantly increased the phosphorylation of insulin receptor (INSR) and AKT, but not ERK. After starvation, acute AKT and ERK signaling stimulated by 0.2 - 20 nM insulin was attenuated. INSR protein was significantly downregulated by hyperinsulinemia in a insulin-dose-dependent manner. Surface INSR was reduced proportionally to total INSR levels. Mechanistically, we found that hyperinsulinemia strongly downregulated Insr mRNA, which was correlated with increased threonine 24 phosphorylation of FOXO1. Interestingly, 6h starvation reversed the effects of high insulin on basal phosphorylation of INSR, AKT and FOXO1, and Insr transcription. Using RNAseq, bioinformatics, and follow-up RNAi studies, we identified SIN3A as a negative regulator of Insr mRNA levels and JUND, MAX and MXI as positive regulators of Irs2 mRNA. We validated our in vitro results by determining that INSR levels in mouse skeletal muscle were negatively correlated with circulating insulin in vivo. Together, our findings shed new light on the mechanisms underlying hyperinsulinemia-induced insulin resistance in muscle cells, which are likely to be relevant in the pathogenesis of type 2 diabetes.

2020-12-31 | GSE147422 | GEO

Glycolysis downregulation is a hallmark of HIV-1 latency and sensitizes infected cells to oxidative stress

Project description:Glycolysis downregulation is a hallmark of HIV-1 latency and sensitizes infected cells to oxidative stress

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Loss of 5-hydroxymethylcytosine is an epigenetic hallmark of melanoma

Project description:DNA methylation at the 5-position of cytosine (5-mC) is a key epigenetic mark critical for varius biological and pathological processes. 5-mC can be converted to 5-hydroxymethylcytosine (5-hmC) by the Ten-Eleven Translocation (TET) family of DNA hydroxylases. Here we report that "loss of 5-hmC" is an epigenetic hallmark of melanoma with diagonostic and prognostic implications. Genome-wide mapping of 5-hmC in nevi and melanomas for the first time revealed loss of 5-hmC landscape in the melanoma epigenome. Downregulation of Isocitrate Dehydrogenase 2 (IDH2) and TET family enzymes proved to be one of the mechanisms underlying the loss of 5-hmC during melanoma development, and rebuilding the 5-hmC landscape in the melanoma epigenome by reintroducing active TET2 or IDH2 suppressed melanoma growth and increased tumor-free survival. Thus, our study establishes that "loss of 5-hmC" is a new epigenetic hallmark of melanoma and links IDH and TET family enzymes-mediated 5-hmC putative tumor suppressor pathway to the suppression of melanoma progression. Determine the genome-wide distribution of 5mC and 5hmC in benign nevus tissue, melanoma tissue, A2058 MOCK cells (overexpressing empty vector), A2058 TET2 cells (overexpressing wild type human TET), and A2058 TET2M cells (overexpressing mutant human TET).

2012-09-18 | E-GEOD-38231 | biostudies-arrayexpress

Acetytransferase P300 impairs insulin signaling in obesity

Project description:Insulin resistance is the hallmark of obese and type 2 diabetes patients. Defective insulin sensitivity in the liver results in increased glucsoe production, which is the major cause of hyperglycemia in diabetic patients. Increased lipopolysaccharide (LPS) leakage from the gut of diet-induced obesity causes insulin resisitance; moreover, activation of deacetylase Sirtuin1 restore insulin sensitivity in obesity. However, the mechanism resulting in insulin resistance by LPS remains poorly understood. Here, we show that Ep300 (P300) harboring an intrinsic acetyltransferase activity was rapidly induced in the liver of animals fed a high-fat diet, and the induction of Ep300 is through LPS-stimulated activation of ER stress. Induced Ep300 impairs insulin signaling by acetylating mediators in insulin signaling. Inhibition of P300 acetyltransferase activity improves insulin signaling. Thus, Ep300 acetyltransferase activity is a therapeutic target.

2017-05-08 | GSE86108 | GEO

RNA-seq of brown adipocyte mouse cells treated with different concentrations of DNA origami structures with organized insulin molecules or free insulin molecules against untreated controls

Project description:Insulin binds the insulin receptor (IR), which in turn has showed to form nanoclusters at the cell membrane. Trying to exploit the nanoscale spatial organization of IR, we developed rod-like insulin-DNA-origami nanostructures carrying different numbers of insulin molecules. These structures (referred to as NanoRods, or NR) were then utilized to investigate receptor activity to spatial distribution of insulin molecules. One part of this investigation was to study the transcriptional response of brown adipocytes treated with NR bound to one insulin (NR-1) and NR bound to seven insulin (NR-7), and compare to untreated controls. Furthermore, free insulin was also used to ensure that similar pathways were activated when using NR-bound insulin.

2023-07-03 | E-MTAB-12160 | biostudies-arrayexpress

Reduced insulin secretion in WFS1-deficient mice may be related to downregulation of Trpm5

Project description:Wolfram syndrome, an autosomal recessive disorder characterized by juvenile-onset diabetes mellitus and optic atrophy, is caused by mutations in the WFS1 gene. WFS1 encodes an endoplasmic reticulum resident transmembrane protein. The Wfs1-null mice exhibit progressive insulin deficiency and diabetes. The aim of the present study was to describe the insulin secretion and transcriptome of pancreatic islets in WFS1-deficient mice. WFS1-deficient (Wfs1KO) mice had considerably less pancreatic islets than heterozygous (Wfs1HZ) or wild-type (WT) mice. Wfs1KO pancreatic islets secreted less insulin after stimulation with 2 and 10 mM glucose and with tolbutamide solution compared to WT and Wfs1HZ islets, but not after stimulation with 20 mM glucose. Differences in proinsulin amount were not statistically significant although there was a trend that Wfs1KO had an increased level of proinsulin. After stimulation with 2 mM glucose solution the proinsulin/insulin ratio in Wfs1KO was significantly higher than that of WT and Wfs1HZ. RNA-seq from pancreatic islets found melastatin-related transient receptor potential subfamily member 5 protein gene (Trpm5) to be downregulated in WFS1-deficient mice. Functional annotation of RNA sequencing results showed that WFS1 deficiency influenced significantly the pathways related to tissue morphology, endocrine system development and function, molecular transport network. These findings suggest an interactive role of WFS1 and TRPM5 in insulin secretion. 12 samples: three genotypes, 4 individuals in each genotype

2015-02-14 | E-GEOD-65929 | biostudies-arrayexpress

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