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Regulation of Expression Occurs at Multiple Steps02:24

Regulation of Expression Occurs at Multiple Steps

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Gene expression can be regulated at almost every step from gene to protein. Transcription is the step that is most commonly regulated. This involves the binding of proteins to short regulatory sequences on the DNA. This association can either promote or inhibit the transcription of a gene associated with the respective sequence.
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The gene expression in cells is regulated at different stages: (i) transcription, (ii) RNA processing, (iii) RNA localization, and (iv) translation. Transcriptional regulation is mediated by regulatory proteins such as transcription factors, activators, or repressors—these control gene expression by initiating or inhibiting the transcription of genes. Once a precursor or pre-mRNA is produced, it undergoes post-transcriptional modification, including 5' capping, splicing, and the...
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In eukaryotes, transcription and translation are compartmentalized; an mRNA is first synthesized in the nucleus and then selectively transported to the cytoplasm for protein synthesis. Before transport, a pre-mRNA undergoes several steps of post-transcriptional modifications including splicing, 5' capping, and the addition of a poly-adenine tail. Various proteins bind to the pre-mRNA during these modifications. The mRNA transport takes place with the help of multiple proteins playing...
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In eukaryotic cells, nascent mRNA transcripts need to undergo many post-transcriptional modifications to reach the cell cytoplasm and translate into functional proteins. For a long time, transcription and pre-mRNA processing were considered two independent events that occur sequentially in the cell. However, it has now been well established that transcription and pre-mRNA processing are two simultaneous processes that are precisely regulated inside the cell.
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Related Experiment Video

Updated: May 29, 2025

Characterizing Histone Post-translational Modification Alterations in Yeast Neurodegenerative Proteinopathy Models
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Neuron-Specific Glycine Metabolism Links Transfer RNA Epitranscriptomic Regulation to Complex Behaviors.

Jennifer Blaze1,2, Viviana Dolores Evans1, Jessica Abigail Feria Pliego3

  • 1Department of Psychiatry, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York.

Biological Psychiatry Global Open Science
|February 6, 2025
PubMed
Summary

Neuronal Nsun2 depletion alters complex behaviors relevant to neuropsychiatric disorders by affecting glycine metabolism or transfer RNA (tRNA) regulation. These findings highlight potential new therapeutic targets for brain conditions.

Keywords:
Cell metabolismEpitranscriptomeGlycineNeuropsychiatrictRNAs

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Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Neuropsychiatric diseases often exhibit treatment resistance, necessitating novel mechanism-based therapies.
  • Transfer RNA (tRNA) epitranscriptomics, specifically the role of Nsun2 methyltransferase, is a potential therapeutic avenue.
  • Nsun2 depletion in neurons affects complex behaviors, but the underlying mechanisms (tRNA dysregulation vs. metabolic shifts) remain unclear.

Purpose of the Study:

  • To investigate the link between neuronal Nsun2 ablation, glycine metabolism, tRNA regulation, and neuropsychiatric phenotypes.
  • To model the effects of Nsun2 deficiency by manipulating glycine cleavage system and tRNA dosage.
  • To analyze behavioral changes, including cognition, anxiety, and despair, in response to these molecular alterations.

Main Methods:

  • Utilized cell type-specific ablation of the glycine cleavage system (Gldc) and neuronal Nsun2 deletion in mice.
  • Employed drug-induced phosphoactivation of stress response translation initiation factors.
  • Disrupted NSUN2-regulated glycine tRNAs and monitored extracellular glycine levels using FRET sensors.
  • Conducted behavioral phenotyping for cognition, anxiety-like behavior, and behavioral despair.

Main Results:

  • Neuron-specific ablation of Gldc led to increased motivated escape behaviors, mirroring phenotypes in Nsun2-deficient mice due to elevated cortical glycine.
  • No similar behavioral changes were observed with tunicamycin treatment or decreased glycine tRNA gene dosage.
  • Extracellular glycine levels in the hippocampus remained dynamic in Nsun2-deficient brains during neuronal activity.

Conclusions:

  • Alterations in neuronal glycine metabolism, via glycine cleavage system ablation, induce behavioral changes relevant to neuropsychiatric phenotypes.
  • Disruption of the tRNA regulome also impacts behaviors associated with neuropsychiatric conditions.
  • These findings establish a connection between glycine metabolism, tRNA regulation, and complex behaviors in the context of neurological disorders.