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Describing a Transcription Factor Dependent Regulation of the MicroRNA Transcriptome
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Describing a Transcription Factor Dependent Regulation of the MicroRNA Transcriptome

Published on: June 15, 2016

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RPA1 binding to NRF2 switches ARE-dependent transcriptional activation to ARE-NRE-dependent repression

Pengfei Liu1, Montserrat Rojo de la Vega1, Saad Sammani2

  • 1Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85721.

Proceedings of the National Academy of Sciences of the United States of America
|October 13, 2018
PubMed

Insights

Nuclear factor erythroid 2-related factor 2 (NRF2) can repress gene transcription. This newly discovered NRF2-RPA1-ARE-NRE pathway regulates diverse genes and impacts vascular integrity, revealing a novel suppressive function for NRF2.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Gene Regulation

Background:

  • Nuclear factor erythroid 2-related factor 2 (NRF2) is known to activate gene transcription by binding to antioxidant response elements (AREs) with small musculoaponeurotic fibrosarcoma proteins (sMAFs).
  • The role of NRF2 in transcriptional repression has not been previously reported.

Purpose of the Study:

  • To investigate and characterize a novel mechanism of NRF2-mediated gene repression.
  • To identify the DNA elements and protein interactions involved in NRF2-dependent transcriptional repression.

Main Methods:

  • Identification of a novel DNA sequence, the NRF2-replication protein A1 (RPA1) element (NRE), flanking the ARE.
  • Demonstration of RPA1 competing with sMAF for NRF2 binding, forming an NRF2-RPA1 complex.
  • Genome-wide in silico and RNA-seq analyses to identify NRF2-RPA1-ARE-NRE regulated genes.
  • Preclinical models of inflammatory lung injury to assess the role of NRF2-mediated repression in vivo.

Main Results:

  • A novel NRF2-mediated gene repression mechanism involving the NRF2-RPA1-ARE-NRE complex was described.
  • This complex negatively regulates a broad range of genes with diverse functions, indicating a fundamental cellular process.
  • Repression of MYLK (myosin light chain kinase) by this complex was shown to disrupt vascular integrity in inflammatory lung injury models.

Conclusions:

  • NRF2 possesses a previously unrecognized gene-suppressive function mediated by the NRF2-RPA1-ARE-NRE complex.
  • This mechanism highlights a fundamental aspect of gene regulation with broad implications in physiological and pathological conditions.
  • The findings underscore the translational significance of NRF2-mediated transcriptional repression, particularly in inflammatory diseases.
Keywords:
MYLK/MLCKNRF2RPA1acute lung injurytranscriptional regulation

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