Loss of β-cell identity and diabetic phenotype in mice caused by disruption of CNOT3-dependent mRNA deadenylation

Mostafa, Dina; Yanagiya, Akiko; Georgiadou, Eleni; Wu, Yibo; Stylianides, Theodoros; Rutter, Guy A.; Suzuki, Toru; Yamamoto, Tadashi

doi:10.1038/s42003-020-01201-y

Cited by 13 publications

(13 citation statements)

References 74 publications

(130 reference statements)

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“…In other studies of mice with organ-specific knock out of CNOT3 loss of expression in pancreatic β-cells impairs glucose tolerance and leads to reduced β-cell mass and, eventually, diabetes [411]. This is consistent with the observation that CNOT3 is essential for murine β-cell maturation and that it is dysregulated in diabetic db/db mice [411].…”

Section: The Cnot Complex and Human Diseasesupporting

confidence: 86%

“…The mice also exhibit hyperinsulinemia, hyperglycemia, insulin resistance, and glucose intolerance coupled with difficulties in the maintenance of body temperature [410]. In other studies of mice with organ-specific knock out of CNOT3 loss of expression in pancreatic β-cells impairs glucose tolerance and leads to reduced β-cell mass and, eventually, diabetes [411]. This is consistent with the observation that CNOT3 is essential for murine β-cell maturation and that it is dysregulated in diabetic db/db mice [411].…”

Section: The Cnot Complex and Human Diseasementioning

confidence: 99%

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The Regulatory Properties of the Ccr4–Not Complex

Hagkarim

Grand

2020

Cells

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The mammalian Ccr4–Not complex, carbon catabolite repression 4 (Ccr4)-negative on TATA-less (Not), is a large, highly conserved, multifunctional assembly of proteins that acts at different cellular levels to regulate gene expression. In the nucleus, it is involved in the regulation of the cell cycle, chromatin modification, activation and inhibition of transcription initiation, control of transcription elongation, RNA export, nuclear RNA surveillance, and DNA damage repair. In the cytoplasm, the Ccr4–Not complex plays a central role in mRNA decay and affects protein quality control. Most of our original knowledge of the Ccr4–Not complex is derived, primarily, from studies in yeast. More recent studies have shown that the mammalian complex has a comparable structure and similar properties. In this review, we summarize the evidence for the multiple roles of both the yeast and mammalian Ccr4–Not complexes, highlighting their similarities.

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Section: The Cnot Complex and Human Diseasesupporting

confidence: 86%

Section: The Cnot Complex and Human Diseasementioning

confidence: 99%

The Regulatory Properties of the Ccr4–Not Complex

Hagkarim

Grand

2020

Cells

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“…In brief, protein was extracted from the adipose samples by first lysis in a buffer with protease inhibitor, followed by homogenization with a glass dounce and sonication. The protein fraction was isolated from the homogenate by centrifugation, and processed for assay on a liquid chromatography tandem mass spectrometry (LC-M/MS) using a modified Phase Transfer Surfactant Method as described in Mostafa et al 96, 97 Samples were measured using a Q Exactive Plus Orbitrap LC–MS/MS System (Thermo Fisher). For each sample, 600 ng was injected and the samples were measured with data-independent acquisition (DIA).…”

Section: Methodsmentioning

confidence: 99%

Genetic Loci and Metabolic States Associated With Murine Epigenetic Aging

Mozhui

et al. 2021

Preprint

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DNA methylation (DNAm) clocks are accurate molecular biomarkers of aging. However, the clock mechanisms remain unclear. Here, we used a pan-mammalian microarray to assay DNAm in liver from 339 predominantly female mice belonging to the BXD family. We computed epigenetic clocks and maximum lifespan predictor (predicted-maxLS), and examined associations with DNAm entropy, diet, weight, metabolic traits, and genetic variation. The epigenetic age acceleration (EAA) derived from the clocks, and predicted-maxLS were correlated with lifespan of the BXD strains. Quantitative trait locus (QTL) analyses uncovered significant QTLs on chromosome (Chr) 11 that encompasses the Erbb2/Her2 oncogenic region, and on Chr19 that contains a cytochrome P450 cluster. Both loci harbor candidate genes associated with EAA in humans (STXBP4, NKX2-3, CUTC). Transcriptome and proteome analyses revealed enrichment in oxidation-reduction, metabolic, and mitotic genes. Our results highlight loci that are concordant in human and mouse, and demonstrate intimate links between metabolism, body weight, and epigenetic aging.

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“…Ablation of genes encoding individual subunits of the CCR4-NOT complex revealed its roles in various physiological functions. For instance, CNOT3 is required for postnatal liver functions ( 38 ), pancreatic β cell function and identity ( 39 ), maintaining cardiac homeostasis ( 40 ), and bone resorption ( 41 ). CNOT7, a catalytic subunit, has non-redundant functions in spermatogenesis ( 42 , 43 ).…”

Section: Initiation Of the Mrna Decay Pathway By Deadenylationmentioning

confidence: 99%

Regulation of Early Lymphocyte Development via mRNA Decay Catalyzed by the CCR4-NOT Complex

Akiyama

Yamamoto

2021

Front. Immunol.

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Development of lymphocytes is precisely regulated by various mechanisms. In addition to transcriptional rates, post-transcriptional regulation of mRNA abundance contributes to differentiation of lymphocytes. mRNA decay is a post-transcriptional mechanism controlling mRNA abundance. The carbon catabolite repression 4 (CCR4)-negative on TATA-less (NOT) complex controls mRNA longevity by catalyzing mRNA deadenylation, which is the rate-limiting step in the mRNA decay pathway. mRNA decay, regulated by the CCR4-NOT complex, is required for differentiation of pro-B to pre-B cells and V(D)J recombination in pro-B cells. In this process, it is likely that the RNA-binding proteins, ZFP36 ring finger protein like 1 and 2, recruit the CCR4-NOT complex to specific target mRNAs, thereby inducing cell quiescence of pro-B cells. A recent study showed that the CCR4-NOT complex participates in positive selection of thymocytes. Mechanistically, the CCR4-NOT deadenylase complex inhibits abnormal apoptosis by reducing the expression level of mRNAs encoding pro-apoptotic proteins, which are otherwise up-regulated during positive selection. We discuss mechanisms regulating CCR4-NOT complex-dependent mRNA decay in lymphocyte development and selection.

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Loss of β-cell identity and diabetic phenotype in mice caused by disruption of CNOT3-dependent mRNA deadenylation

Cited by 13 publications

References 74 publications

The Regulatory Properties of the Ccr4–Not Complex

The Regulatory Properties of the Ccr4–Not Complex

Genetic Loci and Metabolic States Associated With Murine Epigenetic Aging

Regulation of Early Lymphocyte Development via mRNA Decay Catalyzed by the CCR4-NOT Complex

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