The Transcription Factor NRF2 Has Epigenetic Regulatory Functions Modulating HDACs, DNMTs, and miRNA Biogenesis

Abstract

The epigenetic regulation of gene expression is a complex and tightly regulated process that defines cellular identity and is associated with health and disease processes. Oxidative stress is capable of inducing epigenetic modifications. The transcription factor NRF2 (nuclear factor erythroid-derived 2-like 2) is a master regulator of cellular homeostasis, regulating genes bearing antioxidant response elements (AREs) in their promoters. Here, we report the identification of ARE sequences in the promoter regions of genes encoding several epigenetic regulatory factors, such as histone deacetylases (HDACs), DNA methyltransferases (DNMTs), and proteins involved in microRNA biogenesis. In this research, we study this possibility by integrating bioinformatic, genetic, pharmacological, and molecular approaches. We found ARE sequences in the promoter regions of genes encoding several HDACs, DNMTs, and proteins involved in miRNA biogenesis. We confirmed that NRF2 regulates the production of these genes by studying NRF2-deficient cells and cells treated with dimethyl fumarate (DMF), an inducer of the NRF2 signaling pathway. In addition, we found that NRF2 could be involved in the target RNA-dependent microRNA degradation (TDMD) of miR-155-5p through its interaction with Nfe2l2 mRNA. Our data indicate that NRF2 has an epigenetic regulatory function, complementing its traditional function and expanding the regulatory dimensions that should be considered when developing NRF2-centered therapeutic strategies.

Unveiling the impact of DNA methylation machinery: Dnmt1 and Dnmt3a in orchestrating oocyte development and cellular homeostasis

“…The p62/SQSTM1-Keap1-Nrf2 axis is linked to selective autophagy and regulated by post-translational modifications such as sequential phosphorylation and ubiquitination of p62/SQSTM1 (Kageyama et al, 2018). It is known that the transcription factor NRF2 has epigenetic regulatory functions modulating Dnmts and other related enzymes (Silva-Llanes et al, 2023). We recently, showed that inhibiting either Dnmt1 or Dnmt3a caused increased p62 levels in embryos (Uysal et al, 2023).…”

Advances in Understanding the Role of NRF2 in Liver Pathophysiology and Its Relationship with Hepatic-Specific Cyclooxygenase-2 Expression

“…Another degradation mechanism for NRF2 was proposed involving inositol requiring enzyme 1 (IRE1)/E3 ubiquitin ligase synoviolin (HRD1) present in the ER and whose expression is enhanced by activation of the X-box binding protein 1 (XBP1)-HRD1 arm under conditions of reticulum stress [ 30 ] ( Figure 2 ). Finally, indirect regulation may occur through the modulation of miRNAs controlling KEAP1 and CUL3 [ 31 ].…”

“…Furthermore, miRNAs capable of regulating NFE2L2 were identified in the context of cancer [ 52 ] and cardiovascular or neurodegenerative diseases [ 53 , 54 ]. Recently, thanks to the analysis of embryonic fibroblasts derived from NRF2-deficient mice, or with the use of activators that modulate the KEAP1 and GSK3 pathways in hippocampal neurons, it was shown that NRF2 can in turn regulate epigenetic mechanisms by controlling the expression of HDAC1 , SIRT1, and DNA (cytosine-5)-methyltransferases ( DNMTs ) that have ARE elements in their promoters [ 31 ]. The modulation of oxidative stress-associated miRNAs (redoximiRs), such as miR-27c-3p, miR-27b-3p, miR-128-3p and miR-155-5p, was also demonstrated [ 55 ].…”

“…The modulation of oxidative stress-associated miRNAs (redoximiRs), such as miR-27c-3p, miR-27b-3p, miR-128-3p and miR-155-5p, was also demonstrated [ 55 ]. These redoximiRs are able to modulate NRF2 levels [ 56 ]; in turn, NRF2 is able to modulate the action of these miRNAs through direct degradation [ 57 ] or by modulating their biogenesis [ 31 ] ( Figure 3 ).…”

Aging, NRF2, and TAU: A Perfect Match for Neurodegeneration?

“…Concerning the transcription factor NRF2, aging is the main cause of the decline in its activity, since it has been shown that its capacity to induce the expression of antioxidant and detoxifying enzymes decreases with age [ 21 , 22 , 23 ]. Given that NRF2 is a pleiotropic transcription factor involved in the modulation of more than 250 genes associated with biotransformation (which is the alteration of a substance within the body) and detoxification [ 24 , 25 ], redox homeostasis [ 26 , 27 ], lipid and carbohydrate metabolism [ 28 , 29 ], inflammation [ 30 , 31 , 32 , 33 ], epigenetics [ 34 ], autophagy [ 35 , 36 , 37 ], and proteasomes [ 32 , 38 , 39 , 40 ] ( Figure 3 ), which are mechanisms involved in aging, there is clearly an interdependence between aging and NRF2. In this review, we will focus on some of these relevant points, such as genomic instability, loss of proteostasis/autophagy, cellular senescence, stem cell exhaustion, inflammation, and mitochondrial dysfunction.…”