Pathway Analysis of ChIP-Seq-Based NRF1 Target Genes Suggests a Logical Hypothesis of their Involvement in the Pathogenesis of Neurodegenerative Diseases

Abstract

Nuclear respiratory factor 1 (NRF1) serves as a transcription factor that activates the expression of a wide range of nuclear genes essential for mitochondrial biogenesis and function, including mitochondrial respiratory complex subunits, heme biosynthetic enzymes, and regulatory factors involved in the replication and transcription of mitochondrial DNA. Increasing evidence indicates that mitochondrial function is severely compromised in the brains of aging-related neurodegenerative diseases. To identify the comprehensive set of human NRF1 target genes potentially relevant to the pathogenesis of neurodegenerative diseases, we analyzed the NRF1 chromatin immunoprecipitation followed by deep sequencing (ChIP-Seq) dataset retrieved from the Encyclopedia of DNA Elements (ENCODE) project. Overall, we identified 2,470 highly stringent ChIP-Seq peaks on protein-coding genes in SK-N-SH human neuroblastoma cells. They were accumulated in the proximal promoter regions with an existence of the NRF1-binding consensus sequence. The set of ChIP-Seq-based NRF1 target genes included known NRF1 targets such as EIF2S1, EIF2S2, CYCS, FMR1, FXR2, E2F6, CD47, and TOMM34. By pathway analysis, the molecules located in the core pathways related to mitochondrial respiratory function were determined to be highly enriched in NRF1 target genes. Furthermore, we found that NRF1 target genes play a pivotal role in regulation of extra-mitochondrial biological processes, including RNA metabolism, splicing, cell cycle, DNA damage repair, protein translation initiation, and ubiquitin-mediated protein degradation. We identified a panel of neurodegenerative disease-related genes, such as PARK2 (Parkin), PARK6 (Pink1), PARK7 (DJ-1), and PAELR (GPR37) for Parkinson’s disease, as well as PSENEN (Pen2) and MAPT (tau) for Alzheimer’s disease, as previously unrecognized NRF1 targets. These results suggest a logical hypothesis that aberrant regulation of NRF1 and its targets might contribute to the pathogenesis of human neurodegenerative diseases via perturbation of diverse mitochondrial and extra-mitochondrial functions.

Lmx1a and Lmx1b regulate mitochondrial functions and survival of adult midbrain dopaminergic neurons

“…Nrf1, in collaboration with PGC-1α, controls oxidative phosphorylation through the expression of many key nuclear-encoded mitochondrial genes, including all cytochrome c oxidase nuclearencoded subunit genes (37,38). Interestingly, several PD-related genes such as PARK2 (Parkin), PARK6 (Pink1), PARK7 (DJ-1), and PAELR (GPR37) have been identified as NRF1 targets (39). These data indicate that Lmx1a/b activity could influence mitochondrial functions, either directly or indirectly through Nrf1 (or other transcriptional cascades).…”

Genome-Wide Analysis of Wilms’ Tumor 1-Controlled Gene Expression in Podocytes Reveals Key Regulatory Mechanisms

“…Interestingly, NRF1 activates transcription of genes involved in mitochondrial function, protein catabolism, and cell-cycle control, corroborating the results of our GO enrichment analysis for class 1 peaks. 24,25 The analysis of class 2 nonpromoter peaks confirmed a highly significant enrichment of Homeobox, Tcf-family, MAFB, and Fox-class sites, suggesting that these factors may cooperate with WT1 to activate podocyte-specific enhancers and constitute a podocyte-TF network ( Figure 3E). Indeed, as frequently found in such networks, WT1 targeted these TF genes to activate their expression in podocytes ( Figure 3F).…”

Neurochemicals, Behaviours and Psychiatric Perspectives of Neurological Diseases

“…Age dependent behavioural abnormalities such as: impaired rotarod performance, abnormal leg-clasping reflex, and hyperactivity were observed in NRF1 deficient mice. Moreover, corresponding brain atrophy due to apoptosis in NRF1 deficient mice was observed [110][111][112]. Mutation in APOE4 that blocks NRF1 binding to the exon 4 of the gene has been recently linked to AD [113].…”

“…Integrated pathway analysis of an NRF1 ChIP-Seq dataset identified MAPT (tau), PAELR (GPR37), PARK2 (Parkin), PARK6 (Pink1), PARK7 (DJ-1), and PSENEN (Pen2) genes which are related to AD and PD. These could be novel targets of NRF1 [110]. Disruption of NRF1 orthologs in Drosophila and Zebrafish causes severe neurological defects confirming its role in functional maintenance of the nervous system.…”

“…Increasing evidences suggest that mitochondrial function is severely hampered in neurodegenerative diseases where NRF1 might play a vital role. [110]. Integrated pathway analysis of an NRF1 ChIP-Seq dataset identified MAPT (tau), PAELR (GPR37), PARK2 (Parkin), PARK6 (Pink1), PARK7 (DJ-1), and PSENEN (Pen2) genes which are related to AD and PD.…”