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Insulin receptor associates with promoters genome-wide and regulates gene expression [ChIP-seq]

ABSTRACT: ChIP-seq analysis demonstrates an association of insulin receptor (IR) and RNA polymerase II on chromatin, with striking enrichment at gene promoters.

ORGANISM(S): Homo sapiens

PROVIDER: GSE107335 | GEO | 2019/04/04

REPOSITORIES: GEO

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Rescue of insulin receptor condensates in insulin resistant cells

Project description:Insulin resistance is accompanied by chronic hyperinsulinemia and is associated with type 2 diabetes and other metabolic syndromes in a substantial portion of the population. The risk factors and features of insulin resistance have been thoroughly described but its mechanistic triggers are still under study. Here we consider a condensate model for insulin receptor (IR) function in normal conditions and when dysregulated in chronic hyperinsulinemia-induced insulin resistance. We find that IR is incorporated into liquid-like condensates at the plasma membrane, in the cytoplasm and in the nucleus of liver cells, and provide evidence for insulin-dependent IR function in condensates. Insulin stimulation promotes further incorporation of IR into these dynamic condensates in insulin sensitive cells, which form and dissolve on short, sub-minute time-scales. In contrast, insulin stimulation does not promote further incorporation of IR into condensates in insulin resistant cells, where IR molecules within condensates exhibit less dynamic behavior. Metformin treatment of insulin resistant cells rescues IR condensate dynamics and insulin responsiveness. Insulin resistant cells experience high levels of oxidative stress, which causes reduced condensate dynamics, and treatment of these cells with metformin reduces ROS levels and returns condensates to their normal dynamic behavior. The condensate model we propose can account for features of normal and dysregulated insulin response and has implications for improved therapeutic approaches to insulin resistance.

2023-07-28 | GSE181096 | GEO

Insulin receptor associates with promoters genome-wide and regulates gene expression [RNA-seq]

Project description:RNA-seq analysis identifies transcripts regulated by insulin treatment.

2019-04-04 | GSE107334 | GEO

nuclear insulin receptor-associated proteins in lung cancer cells

Project description:We have demonstrated that the communication between macrophages and lung cancer cells via macrophage-derived insulin-like growth factor 2 (IGF2) drives lung cancer progression. As a mechanism of action, we found that insulin receptor (IR) was rapidly activated and translocated to the cytosol and nucleus in response to IGF2 stimulation, and nuclearly translocated IR was associated with chromatin. Therefore, we carried out LC-MS/MS analysis to identify the nuclear proteins associated with IR.

2024-06-14 | PXD051519 | Pride

The dynamic clustering of insulin receptor underlies its signaling and is disrupted in insulin resistance

Project description:Insulin receptor (IR) signaling is central to normal metabolic control and is dysregulated in metabolic diseases such as type 2 diabetes. We report here that IR is incorporated into dynamic clusters at the plasma membrane, in the cytoplasm and in the nucleus of human hepatocytes and adipocytes. Insulin stimulation promotes further incorporation of IR into these dynamic clusters in insulin-sensitive cells but not in insulin-resistant cells, where both IR accumulation and dynamic behavior are reduced. Treatment of insulin-resistant cells with metformin, a first-line drug used to treat type 2 diabetes, can rescue IR accumulation and the dynamic behavior of these clusters. This rescue is associated with metformin’s role in reducing reactive oxygen species that interfere with normal dynamics. These results indicate that changes in the physico-mechanical features of IR clusters contribute to insulin resistance and have implications for improved therapeutic approaches.

2022-12-05 | MTBLS6505 | MetaboLights

Insulin receptor associates with promoters genome-wide and regulates gene expression

Project description:Insulin receptor associates with promoters genome-wide and regulates gene expression

| PRJNA419799 | ENA

Insulin Receptor-Overexpressing beta-Cells Ameliorate Hyperglycemia in Diabetic Rats through Wnt Signaling Activation

Project description:To investigate the therapeutic efficacy of beta-cells with IR manipulation, a plasmid containing human IR was stably introduced into rat beta-cell line INS-1 cells (namely, INS-IR cells). In the INS-IR cells, the role of cross-talk between insulin and Wnt signaling pathways in improving the functionality of beta-cells was investigated.

2013-06-11 | E-MEXP-3836 | biostudies-arrayexpress

Insulin Receptor Associates with Promoters Genome-wide and Regulates Gene Expression.

Project description:Insulin receptor (IR) signaling is central to normal metabolic control and dysregulated in prevalent chronic diseases. IR binds insulin at the cell surface and transduces rapid signaling via cytoplasmic kinases. However, mechanisms mediating long-term effects of insulin remain unclear. Here, we show that IR associates with RNA polymerase II in the nucleus, with striking enrichment at promoters genome-wide. The target genes were highly enriched for insulin-related functions including lipid metabolism and protein synthesis and diseases including diabetes, neurodegeneration, and cancer. IR chromatin binding was increased by insulin and impaired in an insulin-resistant disease model. Promoter binding by IR was mediated by coregulator host cell factor-1 (HCF-1) and transcription factors, revealing an HCF-1-dependent pathway for gene regulation by insulin. These results show that IR interacts with transcriptional machinery at promoters and identify a pathway regulating genes linked to insulin's effects in physiology and disease.

| S-EPMC6478446 | biostudies-literature

Muscle Specific Insulin Receptor Overexpression Protects Mice from Diet-Induced Glucose Intolerance but Leads to Post-Receptor Insulin Resistance

Project description:Skeletal muscle insulin resistance is a prominent early feature in the pathogenesis of type 2 diabetes (T2D). In attempt to overcome this defect, we generated mice overexpressing insulin receptors (IR) specifically in skeletal muscle (IRMOE). On normal chow, IRMOE mice have similar body weight as controls, but an increase in lean mass and glycolytic muscle fibers and reduced fat mass. IRMOE mice also show higher basal phosphorylation of IR, IRS-1 and Akt in muscle and improved glucose tolerance compared to controls. When challenged with high fat diet (HFD), IRMOE mice are protected from diet-induced obesity. This is associated with reduced inflammation in fat and liver, improved glucose tolerance and improved systemic insulin sensitivity. Surprisingly, however, in both chow and HFD-fed mice, insulin stimulated Akt phosphorylation is significantly reduced in muscle of IRMOE mice, indicating post-receptor insulin resistance. RNA sequencing reveals downregulation of several post-receptor signaling proteins that contribute to this resistance. Thus, enhancing early insulin signaling in muscle by overexpression of the insulin receptor protects mice from diet-induced obesity and its effects on glucose metabolism. However, chronic overstimulation of this pathway leads to post-receptor desensitization, indicating the critical balance between normal signaling and hyperstimulation of the insulin signaling pathway.

2020-09-01 | GSE149662 | GEO

Leucine-973 is a Crucial Residue Differentiating Insulin and IGF-1 Receptor Signaling

Project description:Insulin and IGF-1 receptors (IR/IGF1R) are highly homologous and share similar signaling systems, but each has a unique physiological role, with IR primarily regulating metabolic homeostasis and IGF1R regulating mitogenic control and growth. Here, we show that replacement of a single amino acid at position 973, just distal to the NPEY motif in the intracellular juxtamembrane region, from leucine, which is highly-conserved in IRs, to phenylalanine, the highly-conserved homologous residue in IGF1Rs, results in decreased IRS-1-PI3K-Akt-mTORC1 signaling and increased of Shc-Gab1-MAPK-cell cycle signaling. As a result, cells expressing L973F-IR exhibit decreased insulin-induced glucose uptake, increased cell growth and impaired receptor internalization. Mice with knockin of the L973F-IR show similar alterations in signaling in vivo, and this leads to decreased insulin sensitivity, a modest increase in growth and decreased weight gain when challenged with high-fat diet. Thus, leucine973 in the juxtamembrane region of the IR acts is a crucial residue differentiating IR signaling from IGF1R signaling.

2022-12-21 | PXD038649 | Pride

Expression data in subcutaneous xenografts of Huh7 cells overexpressing or not insulin receptor isoform A

Project description:Insulin receptor isoform A (IR-A) is overexpressed in human hepatocellular carcinoma. We used microarrays to investigate gene expression patterns in subcutaneous xenografts derived from Huh7 stably overexpressing IR-A

2018-03-13 | GSE111707 | GEO

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