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

ABSTRACT

Members of the cap’n’collar (CNC) family of transcription factors, including Nrf1 and Nrf2, heterodimerize with small Maf (sMaf) proteins (MafF, MafG, and MafK) and regulate target gene expression through CNC-sMaf-binding elements (CsMBEs). We recently developed a unique tethered dimer assessment system combined with small Maf triple-knockout fibroblasts, which enabled the characterization of specific CNC-sMaf heterodimer functions. In this study, we evaluated the molecular function of the tethered Nrf1-MafG (T-N1G) heterodimer. We found that T-N1G activates the expression of proteasome subunit genes, well-known Nrf1 target genes, and binds specifically to CsMBEs in the proximity of these genes. T-N1G was also found to activate genes involved in proteostasis-related pathways, including endoplasmic reticulum-associated degradation, chaperone, and ubiquitin-mediated degradation pathways, indicating that the Nrf1-MafG heterodimer regulates a wide range of proteostatic stress response genes. By taking advantage of this assessment system, we found that Nrf1 has the potential to activate canonical Nrf2 target cytoprotective genes when strongly induced. Our results also revealed that transposable SINE B2 repeats harbor CsMBEs with high frequency and contribute to the target gene diversity of CNC-sMaf transcription factors.

KEYWORDS:

• Nrf1
• Nrf2
• small Maf
• tethered molecule
• CsMBE
• MafG
• transcriptional regulation

Declaration of Interests

The authors declare no conflict of interest.

SUPPLEMENTAL MATERIAL

Supplemental material is available online only.

ACKNOWLEDGMENTS

We thank members of the Department of Integrative Genomics and the Department of Medical Biochemistry for their support and helpful discussions.

This work was supported in part by MEXT/JSPS KAKENHI (grant no. 19H05649 to M.Y. and grant no. 20K07335 to F.K.).

F.K. and M.Y. designed the research. F.K., A.O., N.H., and H.O. conducted the experiments and analyzed the data. F.K. and M.Y. wrote the paper.

We declare no conflicts of interest.