Target Gene Diversity of the Nrf1-MafG Transcription Factor Revealed by a Tethered Heterodimer

Area of Science:

• Molecular Biology
• Transcription Factor Regulation
• Cellular Stress Response

Background:

• Cap'n'collar (CNC) transcription factors, including Nrf1 and Nrf2, form heterodimers with small Maf (sMaf) proteins.
• These CNC-sMaf heterodimers regulate gene expression via CNC-sMaf-binding elements (CsMBEs).
• A novel tethered dimer assessment system was developed to study specific heterodimer functions.

Purpose of the Study:

• To elucidate the molecular function of the tethered Nrf1-MafG (T-N1G) heterodimer.
• To investigate the role of Nrf1-MafG in regulating proteostasis and stress response pathways.
• To explore the potential of Nrf1 to activate Nrf2 target genes under specific conditions.

Main Methods:

• Utilized a unique tethered dimer assessment system.
• Employed small Maf triple-knockout fibroblasts for analysis.
• Evaluated gene expression activation and DNA binding specificity of the T-N1G heterodimer.

Main Results:

• T-N1G specifically activates proteasome subunit gene expression and binds to CsMBEs.
• Nrf1-MafG heterodimers regulate diverse proteostasis pathways, including ER-associated degradation and ubiquitin-mediated degradation.
• Nrf1 can activate canonical Nrf2 target cytoprotective genes upon strong induction.
• Transposable SINE B2 repeats frequently contain CsMBEs, contributing to target gene diversity.

Conclusions:

• The Nrf1-MafG heterodimer plays a significant role in regulating proteostatic stress response genes.
• Nrf1 exhibits functional plasticity, potentially activating Nrf2-dependent genes under high induction.
• CsMBEs within transposable elements contribute to the broad target gene repertoire of CNC-sMaf factors.