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MicroRNA (miRNA) are short, regulatory RNA transcribed from introns (non-coding regions of a gene) or intergenic regions (stretches of DNA present between genes). Several processing steps are required to form biologically active, mature miRNA. The initial transcript, called primary miRNA (pri-mRNA), base-pairs with itself, forming a stem-loop structure. Within the nucleus, an endonuclease enzyme, called Drosha, shortens the stem-loop structure into hairpin-shaped pre-miRNA. After the pre-miRNA...
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MicroRNA (miRNA) are short, regulatory RNA transcribed from introns—non-coding regions of a gene—or intergenic regions—stretches of DNA present between genes. Several processing steps are required to form biologically active, mature miRNA. The initial transcript, called primary miRNA (pri-mRNA), base-pairs with itself forming a stem-loop structure. Within the nucleus, an endonuclease enzyme, called Drosha, shortens the stem-loop structure into hairpin-shaped pre-miRNA. After...
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RNA interference (RNAi) is a process in which a small non-coding RNA molecule blocks the post-transcriptional expression of a gene by binding to its messenger RNA (mRNA) and preventing the protein from being translated.
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Translational regulation in prokaryotes ensures efficient protein synthesis by controlling ribosome access to mRNA. This regulation is mediated by secondary RNA structures, including translational riboswitches, RNA thermometers, and small RNAs (sRNAs), which respond to intracellular and environmental signals to modulate gene expression.Translational RiboswitchesRiboswitches in the leader region of mRNAs can regulate translation by altering the accessibility of the Shine-Dalgarno (SD) sequence,...
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RNA G-quadruplex regulates microRNA-26a biogenesis and function.

Geng Liu1, Wenya Du1, Haixia Xu1

  • 1Division of Endocrinology and Metabolism, National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu 610041, Sichuan, China.

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RNA G-quadruplexes (RG4s) in pre-miR-26a-1 impair microRNA-26a maturation, impacting liver metabolism and insulin sensitivity. Obesity exacerbates this RG4/miR-26a dysregulation, highlighting a novel therapeutic target.

Keywords:
DHX36Insulin sensitivityLiver metabolismObesityRNA structuremiRNA

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Area of Science:

  • Molecular Biology
  • Gene Regulation
  • RNA Structure

Background:

  • RNA G-quadruplexes (RG4s) are implicated in post-transcriptional gene regulation.
  • MicroRNA-26a (miR-26a) is a therapeutic target, but its endogenous regulation is unclear.
  • Pathophysiological roles of RG4s are largely unknown.

Purpose of the Study:

  • Investigate the role of RG4 in miR-26a expression and function.
  • Elucidate the mechanism of RG4-mediated regulation of miR-26a.
  • Explore the RG4/miR-26a axis in the context of obesity and metabolic disease.

Main Methods:

  • Bioinformatic prediction and biophysical/biochemical analysis of RG4 structures in pre-miR-26a-1.
  • In vitro and in vivo studies using RG4 stabilizers, overexpression plasmids, and mouse models (knock-in/knockout).
  • Assessment of RG4 interaction with DEAH-box helicase 36 (DHX36) and quantification in obese mouse livers.

Main Results:

  • Identified an RG4 structure in pre-miR-26a-1 that impairs its maturation and decreases miR-26a levels.
  • Demonstrated that this RG4 regulates hepatic insulin sensitivity and lipid metabolism.
  • Revealed DHX36 binds and unwinds the RG4, enhancing miR-26a maturation; obese mice show decreased miR-26a maturation and DHX36 expression.

Conclusions:

  • Defined a DHX36/RG4/miR-26a regulatory axis crucial in obesity.
  • Highlighted the significant role of RG4 in both physiological and pathological processes.
  • Established a link between RG4 formation, impaired miR-26a function, and metabolic dysfunction in obesity.