Proline exacerbates hepatic gluconeogenesis via paraspeckle-dependent mRNA retention [RIP-Seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1060669 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27408514_1.fastq.gz | Fastqsanger.gz | |||
| SRR27408514_2.fastq.gz | Fastqsanger.gz | |||
| SRR27408515_1.fastq.gz | Fastqsanger.gz | |||
| SRR27408515_2.fastq.gz | Fastqsanger.gz | |||
| SRR27408516_1.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description:Type 2 Diabetes (T2D) is a global health issue characterized by abnormal blood glucose levels and often associated with excessive hepatic gluconeogenesis. Increased circulating non-essential amino acids (NEAAs) are consistently observed in T2D individuals; however, the specific contribution of each amino acid to T2D pathogenesis remains less understood. Here, we reported an unexpected role of the NEAA proline in coordinating hepatic glucose metabolism by modulating paraspeckle, a nuclear structure scaffolded by the long noncoding RNA Neat1. Mechanistically, proline diminished paraspeckles in hepatocytes, liberating the retained mRNA species into cytoplasm for translation, including the mRNAs of Ppargc1a and Foxo1, contributing to enhanced gluconeogenesis and hyperglycemia. We further demonstrated that the proline-paraspeckle-mRNA retention axis existed in diabetic liver samples, and intervening this axis via paraspeckle restoration significantly alleviated hyperglycemia in both female and male diabetic mouse models. Collectively, our results not only delineated a previously unappreciated proline-instigated, paraspeckle-dependent mRNA retention mechanism regulating gluconeogenesis, but also spotlighted proline and paraspeckle as potential targets for managing hyperglycemia. This SuperSeries is composed of the SubSeries listed below.
2024-11-26 | GSE252452 | GEO
Project description:Type 2 Diabetes (T2D) is a global health issue characterized by abnormal blood glucose levels and often associated with excessive hepatic gluconeogenesis. Increased circulating non-essential amino acids (NEAAs) are consistently observed in T2D individuals; however, the specific contribution of each amino acid to T2D pathogenesis remains less understood. Here, we reported an unexpected role of the NEAA proline in coordinating hepatic glucose metabolism by modulating paraspeckle, a nuclear structure scaffolded by the long noncoding RNA Neat1. Mechanistically, proline diminished paraspeckles in hepatocytes, liberating the retained mRNA species into cytoplasm for translation, including the mRNAs of Ppargc1a and Foxo1, contributing to enhanced gluconeogenesis and hyperglycemia. We further demonstrated that the proline-paraspeckle-mRNA retention axis existed in diabetic liver samples, and intervening this axis via paraspeckle restoration significantly alleviated hyperglycemia in both female and male diabetic mouse models. Collectively, our results not only delineated a previously unappreciated proline-instigated, paraspeckle-dependent mRNA retention mechanism regulating gluconeogenesis, but also spotlighted proline and paraspeckle as potential targets for managing hyperglycemia.
2024-11-26 | GSE252451 | GEO
Project description:Type 2 Diabetes (T2D) is a global health issue characterized by abnormal blood glucose levels and often associated with excessive hepatic gluconeogenesis. Increased circulating non-essential amino acids (NEAAs) are consistently observed in T2D individuals; however, the specific contribution of each amino acid to T2D pathogenesis remains less understood. Here, we reported an unexpected role of the NEAA proline in coordinating hepatic glucose metabolism by modulating paraspeckle, a nuclear structure scaffolded by the long noncoding RNA Neat1. Mechanistically, proline diminished paraspeckles in hepatocytes, liberating the retained mRNA species into cytoplasm for translation, including the mRNAs of Ppargc1a and Foxo1, contributing to enhanced gluconeogenesis and hyperglycemia. We further demonstrated that the proline-paraspeckle-mRNA retention axis existed in diabetic liver samples, and intervening this axis via paraspeckle restoration significantly alleviated hyperglycemia in both female and male diabetic mouse models. Collectively, our results not only delineated a previously unappreciated proline-instigated, paraspeckle-dependent mRNA retention mechanism regulating gluconeogenesis, but also spotlighted proline and paraspeckle as potential targets for managing hyperglycemia.
2024-11-26 | GSE252450 | GEO
Project description:Proline exacerbates hepatic gluconeogenesis via paraspeckle-dependent mRNA retention
| PRJNA1060673 | ENA
Project description:Proline exacerbates hepatic gluconeogenesis via paraspeckle-dependent mRNA retention [lncRNA-Seq]
| PRJNA1060680 | ENA
Project description:Direct RNA-RNA interaction between Neat1 and RNA targets, as a mechanism for RNAs paraspeckle retention
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Project description:One of the causes of hyperglycemia in type 2 diabetes is elevated hepatic glucose production. AKT-FOXO1 pathway is primarily involved in the hormonal upregulation of this process, and pharmacological or genetic inhibition of this pathway prevents diabetes in animal models. Here we report that DYRK1B regulates FoxO1 function through phosphorylation to regulate hepatic glucose metabolism. DYRK1B expression is induced by fasting and in diabetic mice. DYRK1B promoted hepatic gluconeogenesis and glucose intolerance in in vivo and in vitro model systems. Liver-specific DYRK1B conditional knockout mice were protected from diet-induced hyperglycemia. Mechanistically, DYRK1B interacted with and phosphorylated FoxO1, primarily at T467S468, which is required for its nuclear localization. DYRK1B inhibited AKT mediated FoxO1 phosphorylation at T24 and S256 and enhanced its nuclear retention. DYRK1B mediated phosphorylation of FoxO1 enhanced the expression of gluconeogenic genes and promoted gluconeogenesis. Treatment with DYRK1B pharmacological inhibitor AZ191 significantly lowered blood glucose levels in diabetic mice. We conclude that DYRK1B is a regulator of glucose metabolism, and its pharmacological inhibition could serve as therapeutic target for treating diabetes.
2025-04-30 | GSE262106 | GEO
Project description:One of the causes of hyperglycemia in type 2 diabetes is elevated hepatic glucose production. AKT-FOXO1 pathway is primarily involved in the hormonal upregulation of this process, and pharmacological or genetic inhibition of this pathway prevents diabetes in animal models. Here we report that DYRK1B regulates FoxO1 function through phosphorylation to regulate hepatic glucose metabolism. DYRK1B expression is induced by fasting and in diabetic mice. DYRK1B promoted hepatic gluconeogenesis and glucose intolerance in in vivo and in vitro model systems. Liver-specific DYRK1B conditional knockout mice were protected from diet-induced hyperglycemia. Mechanistically, DYRK1B interacted with and phosphorylated FoxO1, primarily at T467S468, which is required for its nuclear localization. DYRK1B inhibited AKT mediated FoxO1 phosphorylation at T24 and S256 and enhanced its nuclear retention. DYRK1B mediated phosphorylation of FoxO1 enhanced the expression of gluconeogenic genes and promoted gluconeogenesis. Treatment with DYRK1B pharmacological inhibitor AZ191 significantly lowered blood glucose levels in diabetic mice. We conclude that DYRK1B is a regulator of glucose metabolism, and its pharmacological inhibition could serve as therapeutic target for treating diabetes.
2025-04-30 | GSE263028 | GEO
Project description:MicroRNAs (miRNAs) play crucial roles in physiological functions and diseases such as cancer, but the regulation of their nuclear biogenesis remains poorly understood. Here, BioID on Drosha, the catalytic subunit of the microprocessor complex, revealed its proximity to SFPQ, a multifunctional RNA-binding protein (RBP) notably involved in forming the paraspeckle nuclear condensates. SFPQ depletion impacted both primary and mature miRNA expression, while other crucial paraspeckle proteins or the paraspeckle scaffolding lncRNA NEAT1 did not, indicating a unique paraspeckle-independent role. Comprehensive transcriptomic analyses showed that SFPQ loss broadly affects RNA and miRNA host gene (miRNA HG) expression, influencing both their transcription and stability. Notably, SFPQ protects specific miRNA HGs, including the oncogenic miR-17~92 polycistron, from degradation by the nuclear NEXT-exosome complex. Lastly, we show that high SFPQ is tightly linked with overexpression miR-17~92 and its mature miRNAs across a broad variety of cancers. Our findings reveal a dual role for SFPQ in the regulation of miRNA HGs transcription and stability, as well as its significance in cancers.
2024-09-04 | GSE262127 | GEO
Project description:MicroRNAs (miRNAs) play crucial roles in physiological functions and diseases such as cancer, but the regulation of their nuclear biogenesis remains poorly understood. Here, BioID on Drosha, the catalytic subunit of the microprocessor complex, revealed its proximity to SFPQ, a multifunctional RNA-binding protein (RBP) notably involved in forming the paraspeckle nuclear condensates. SFPQ depletion impacted both primary and mature miRNA expression, while other crucial paraspeckle proteins or the paraspeckle scaffolding lncRNA NEAT1 did not, indicating a unique paraspeckle-independent role. Comprehensive transcriptomic analyses showed that SFPQ loss broadly affects RNA and miRNA host gene (miRNA HG) expression, influencing both their transcription and stability. Notably, SFPQ protects specific miRNA HGs, including the oncogenic miR-17~92 polycistron, from degradation by the nuclear NEXT-exosome complex. Lastly, we show that high SFPQ is tightly linked with overexpression miR-17~92 and its mature miRNAs across a broad variety of cancers. Our findings reveal a dual role for SFPQ in the regulation of miRNA HGs transcription and stability, as well as its significance in cancers.
2024-09-04 | GSE262126 | GEO