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

Hancock, Melissa L.; Meyer, Rebecca C.; Mistry, Meeta; Khetani, Radhika S.; Wagschal, Alexandre; Shin, Taehwan; Sui, Shannan Ho; Näär, Anders M.; Flanagan, John G.

doi:10.1016/j.cell.2019.02.030

Cited by 120 publications

(126 citation statements)

References 68 publications

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“…Unexpectedly, treatment with PEG-insulin elicited a β-cellspecific stimulation of the insulin signalling cascade as well as stimulation of the recently characterised RNA polymerase II mediated pathway 41 (Fig. 6h).…”

Section: Ucn3mentioning

confidence: 88%

Targeted pharmacological therapy restores β-cell function for diabetes remission

et al. 2020

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Dedifferentiation of insulin-secreting β cells in the islets of Langerhans has been proposed to be a major mechanism of β-cell dysfunction. Whether dedifferentiated β cells can be targeted by pharmacological intervention for diabetes remission, and ways in which this could be accomplished, are unknown as yet. Here we report the use of streptozotocin-induced diabetes to study β-cell dedifferentiation in mice. Single-cell RNA sequencing (scRNA-seq) of islets identified markers and pathways associated with β-cell dedifferentiation and dysfunction. Single and combinatorial pharmacology further show that insulin treatment triggers insulin receptor pathway activation in β cells and restores maturation and function for diabetes remission. Additional β-cell selective delivery of oestrogen by Glucagon-like peptide-1 (GLP-1-oestrogen conjugate) decreases daily insulin requirements by 60%, triggers oestrogen-specific activation of the endoplasmic-reticulum-associated protein degradation system, and further increases β-cell survival and regeneration. GLP-1-oestrogen also protects human β cells against cytokineinduced dysfunction. This study not only describes mechanisms of β-cell dedifferentiation and regeneration, but also reveals pharmacological entry points to target dedifferentiated β cells for diabetes remission.There are amendments to this paper NATURE METABoLiSM | VOL 2 | FEBRUARy 2020 | 192-209 | www.nature.com/natmetab 192 Articles NATuRE METAboLiSM autoimmunity in the mSTZ model permits the investigation of the fate of those remaining β cells and the effect of pharmacological treatment on β-cell protection and regeneration.

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Section: Ucn3mentioning

confidence: 88%

Targeted pharmacological therapy restores β-cell function for diabetes remission

et al. 2020

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“…In rat hepatocytes, INSR has been shown to translocate to the nucleus where it regulates calcium signals and proliferation (32). Hancock and colleagues have also investigated the role of INSR in the nucleus of mouse liver cells (33). In their studies, they found that INSR directly associated with genome-wide promoters and regulates gene expression through interactions with RNA polymerase II.…”

Section: Intracellular Igf-1r Insr and Hybrid-rmentioning

confidence: 99%

The IGF/Insulin-IGFBP Axis in Corneal Development, Wound Healing, and Disease

2020

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The insulin-like growth factor (IGF) family plays key roles in growth and development. In the cornea, IGF family members have been implicated in proliferation, differentiation, and migration, critical events that maintain a smooth refracting surface that is essential for vision. The IGF family is composed of multiple ligands, receptors, and ligand binding proteins. Expression of IGF type 1 receptor (IGF-1R), IGF type 2 receptor (IGF-2R), and insulin receptor (INSR) in the cornea has been well characterized, including the presence of the IGF-1R and INSR hybrid (Hybrid-R) in the corneal epithelium. Recent data also indicates that each of these receptors display unique intracellular localization. Thus, in addition to canonical ligand binding at the plasma membrane and the initiation of downstream signaling cascades, IGF-1R, INSR, and Hybrid-R also function to regulate mitochondrial stability and nuclear gene expression. IGF-1 and IGF-2, two of three principal ligands, are polypeptide growth factors that function in all cellular layers of the cornea. Unlike IGF-1 and IGF-2, the hormone insulin plays a unique role in the cornea, different from many other tissues in the body. In the corneal epithelium, insulin is not required for glucose uptake, due to constitutive activation of the glucose transporter, GLUT1. However, insulin is needed for the regulation of metabolism, circadian rhythm, autophagy, proliferation, and migration after wounding. There is conflicting evidence regarding expression of the six IGF-binding proteins (IGFBPs), which function primarily to sequester IGF ligands. Within the cornea, IGFBP-2 and IGFBP-3 have identified roles in tissue homeostasis. While IGFBP-3 regulates growth control and intracellular receptor localization in the corneal epithelium, both IGFBP-2 and IGFBP-3 function in corneal fibroblast differentiation and myofibroblast proliferation, key events in stromal wound healing. IGFBP-2 has also been linked to cellular overgrowth in pterygium. There is a clear role for IGF family members in regulating tissue homeostasis in the cornea. This review summarizes what is known regarding the function of IGF and related proteins in corneal development, during wound healing, and in the pathophysiology of disease. Finally, we highlight key areas of research that are in need of future study.

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“…The most wellstudied example is the forkhead family box O (FOXO) transcription factors which, upon insulin stimulation, are phosphorylated by AKT, bind to 14-3-3 proteins and are thus excluded from the nucleus, limiting their ability to regulate gene expression. 3 Insulin also promotes phosphorylation of FOXK transcription factors 4 and phosphorylation and processing of SREBP-1c, 5 but in these cases, this promotes migration of the FOXKs and SREBP1c into the nucleus where they can regulate transcription.In a recent paper in Cell, Hancock et al 6 propose a new model of insulin regulation of transcription in which IR itself translocates to the nucleus, where it interacts with RNA polymerase II (Pol II) on gene promoters and induces transcription ( Fig. 1, right).…”

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confidence: 99%

“…These IRbound promoters were highly enriched for genes known to be involved in insulin functions in liver, including lipid metabolism, protein synthesis and transcription, as well as for disease pathways where IR signaling is typically dysfunctional such as diabetes and Alzheimer's disease. On the other hand, these sites did not include genes involved in pathways of glucose metabolism, such as gluconeogenesis and glycogen synthesis, which are major metabolic functions of insulin in liver.Through a combination of motif analysis and mass spectrometry, Hancock et al 6 found that the transcriptional coregulator host cell factor-1 (HCF-1) is required for the assembly of IR transcriptional complexes, on at least a subset of genes. Since HCF-1 lacks direct DNA-binding activity, an important step moving forward will be to determine the DNA-binding proteins and transcription factors that mediate IR-HCF-1-Pol II complex formation, how these are regulated and what genes they regulate.…”

mentioning

confidence: 99%

“…Since HCF-1 lacks direct DNA-binding activity, an important step moving forward will be to determine the DNA-binding proteins and transcription factors that mediate IR-HCF-1-Pol II complex formation, how these are regulated and what genes they regulate. Hancock et al 6 suggest that one potential transcription factor mediating IR binding to gene promoters is THAP11, a gene involved in mouse embryonic development, but not previously associated with insulin action. Another possibility may be the FOXK transcription factors, since a recent study by Sakaguchi et al 4 showed that FOXK1 can physically interact with IR and translocate to the nucleus in response to insulin where it controls genes involved in mitochondrial metabolism and cell cycle.…”

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confidence: 99%

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The insulin receptor goes nuclear

2019

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Regulation of gene expression is a major component of insulin action, which is classically thought to occur via phosphorylation, relocalization and/or processing of transcriptional regulators downstream of the insulin receptor (IR) signaling cascade. A recent study in Cell suggests a mechanism by which IR itself translocates to the nucleus and forms transcriptional complexes with RNA polymerase II, host cell factor-1 and transcription factors to directly regulate gene expression, thus adding a new complementary pathway to control this important set of insulin actions.Insulin is the central regulator of metabolism. Insulin controls the balance between fuel utilization and storage, thus maintaining glucose levels during cycles of feeding and fasting. These functions occur in part through effects of insulin to regulate gene expression in a tissue-and cell-specific manner. 1 At the molecular level, insulin binds to insulin receptors (IR) present on cell surface activating IR tyrosine kinase activity. This initiates a broad network of protein phosphorylation, including phosphorylation of IRS-1 leading to activation of the phosphatidylinositol 3-kinase (PI3K)/ AKT pathway involved in most metabolic actions of insulin and phosphorylation of SHC with activation of the RAS/MAP kinase pathway that mediates effects on growth and proliferation. 2 Each of these pathways results in changes in phosphorylation, processing and expression of downstream transcriptional regulators, forming the widely accepted model to explain the effects of insulin to regulate gene expression ( Fig. 1, left). The most wellstudied example is the forkhead family box O (FOXO) transcription factors which, upon insulin stimulation, are phosphorylated by AKT, bind to 14-3-3 proteins and are thus excluded from the nucleus, limiting their ability to regulate gene expression. 3 Insulin also promotes phosphorylation of FOXK transcription factors 4 and phosphorylation and processing of SREBP-1c, 5 but in these cases, this promotes migration of the FOXKs and SREBP1c into the nucleus where they can regulate transcription.In a recent paper in Cell, Hancock et al. 6 propose a new model of insulin regulation of transcription in which IR itself translocates to the nucleus, where it interacts with RNA polymerase II (Pol II) on gene promoters and induces transcription ( Fig. 1, right). IR was identified in the nucleus by binding studies over 40 years ago and suggested to play a role in mRNA export, 7,8 but over the years, interest in a potential role of nuclear IR was lost, and the functional significance of these observations remained elusive. In this new report, mass spectrometry analysis of immunoprecipitated IR from mouse livers revealed an unexpected association of the receptor with multiple subunits of the Pol II complex. ChIP-seq analysis of IR in hepatocytes reveal that 73% of genomic regions where IR peaks were detected overlapped with Pol II occupancy, predominantly on actively transcribed promoter regions. Insulin stimulation led to increased nuclear IR and...

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

Cited by 120 publications

References 68 publications

Targeted pharmacological therapy restores β-cell function for diabetes remission

Targeted pharmacological therapy restores β-cell function for diabetes remission

The IGF/Insulin-IGFBP Axis in Corneal Development, Wound Healing, and Disease

The insulin receptor goes nuclear

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