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Related Concept Videos

Protein Complexes with Interchangeable Parts01:57

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Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
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Cotranslational Protein Translocation

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Lung function associated gene Integrator Complex subunit 12 regulates protein synthesis pathways.

Alexander K Kheirallah1,2, Cornelia H de Moor3, Alen Faiz4

  • 1Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. akk43@cam.ac.uk.

BMC Genomics
|March 25, 2017
PubMed
Summary
This summary is machine-generated.

The Integrator Complex subunit 12 (INTS12) gene regulates protein synthesis and airway biology, impacting human lung function. This finding clarifies the genetic basis for lung function at the 4q24 locus.

Keywords:
Accessible chromatinHistone modificationINTS12Integrator ComplexPathway dysregulationProtein synthesisRegulation of gene expressionTranscriptionsnRNA processing

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Area of Science:

  • Genetics
  • Molecular Biology
  • Pulmonary Medicine

Background:

  • Genetic studies identified a significant locus (4q24) associated with human lung function and Chronic Obstructive Pulmonary Disease.
  • Two candidate genes at this locus, GSTCD and INTS12, were investigated for their role in lung function regulation.
  • INTS12, a component of the Integrator Complex, was previously thought to primarily mediate small nuclear RNA processing.

Purpose of the Study:

  • To investigate the function of INTS12 in lung tissue and its role in regulating lung function.
  • To determine whether INTS12 or GSTCD is the primary gene responsible for the lung function signal at 4q24.
  • To elucidate the genome-wide activities of INTS12 beyond its canonical function.

Main Methods:

  • Analysis of lung tissue polymorphisms correlating with gene expression.
  • INTS12 depletion studies and assessment of small nuclear RNA processing.
  • RNA sequencing (RNAseq) and ChIP-sequencing (ChIPseq) to analyze gene expression and genome-wide binding.
  • Identification of the INTS12 regulome.

Main Results:

  • Polymorphisms at 4q24 associated with lung function correlated with INTS12 expression, not GSTCD expression, in lung tissue.
  • INTS12 depletion caused only minor alterations in small nuclear RNA processing, contrary to previous reports.
  • RNAseq revealed dysregulation of airway biology genes and significant downregulation of protein synthesis pathways upon INTS12 knockdown.
  • ChIPseq demonstrated INTS12 binding across the genome, particularly in active transcription regions, and identified protein synthesis pathway genes as part of the INTS12 regulome.

Conclusions:

  • INTS12 possesses functions beyond canonical small nuclear RNA processing.
  • INTS12 regulates translation through the modulation of protein synthesis pathway gene expression.
  • This study provides a comprehensive genome-wide analysis of INTS12 activities, contributing to the understanding of the genetic basis for lung function at 4q24.