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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE188788 | GEO | 2022/01/30

REPOSITORIES: GEO

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

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

| PRJNA780312 | ENA

Gene expression profile in the tethered Nrf1-MafG (T-N1G) heterodimer-expressing small Maf-deficient cells [RNA-seq]

Project description:To elucidate the function of Nrf1-small Maf heterodimer, we constructed a tethered Nrf1-MafG (T-N1G) heterodimer using a flexible linker peptide and examined its function in the small Maf-deficient mouse embryonic fibroblast (MEF).

2022-01-30 | GSE188787 | GEO

Direct and Specific Functional Evaluation of the Nrf2 and MafG Heterodimer by Introducing a Tethered Dimer into Small Maf-Deficient Cells

Project description:This SuperSeries is composed of the SubSeries listed below.

2019-08-06 | GSE134353 | GEO

Direct and Specific Functional Evaluation of the Nrf2 and MafG Heterodimer by Introducing a Tethered Dimer into Small Maf-Deficient Cells.

Project description:A group of cytoprotective genes is regulated by heterodimers composed of the cap'n'collar (CNC) family member Nrf2 and one of the small Maf (sMaf) proteins (MafF, MafG, or MafK) through the antioxidant response element (ARE, also referred to as the CNC-sMaf binding element [CsMBE]). Many lines of evidence support this model; however, a direct and specific evaluation of the Nrf2-sMaf heterodimer remains to be executed. To address this issue, we constructed a tethered Nrf2-MafG (T-N2G) heterodimer using a flexible linker peptide. We then introduced the T-N2G construct into cells lacking all three sMaf proteins to specifically evaluate the function of the tethered heterodimer without interference from other endogenous CNC-sMaf heterodimers or sMaf homodimers. In response to an Nrf2 activator, diethyl maleate, the T-N2G protein can widely activate the target genes of Nrf2 but not those of Nrf1, such as proteasome subunit genes. Genome-wide binding analysis showed that the T-N2G protein preferentially bound to the CsMBE motifs in the regulatory regions of the Nrf2 target genes. These results provide direct evidence that the Nrf2-MafG heterodimer acts as a transcriptional activator of Nrf2-dependent genes and show that this assay system will be a powerful tool to specifically examine the function of other CNC-sMaf heterodimers.

| S-EPMC6766697 | biostudies-literature

Gene expression profile in the tethered Nrf2-MafG (T-N2G) heterodimer-expressing small Maf-deficient cells [RNA-seq]

Project description:To elucidate the function of Nrf2-small Maf heterodimer, we constructed a tethered Nrf2-MafG (T-N2G) heterodimer using a flexible linker peptide and examined its function in the small Maf-deficient mouse embryonic fibroblast (MEF).

2019-08-06 | GSE134351 | GEO

Genome wide-binding profile of tethered Nrf1-MafG (T-N1G) heterodimers in the small Maf-deficient cells [ChIP-seq]

2022-01-30 | GSE188785 | GEO

Transcription factor Nrf1 is topologically repartitioned across membranes to enable target gene transactivation through its acidic glucose-responsive domains.

Project description:The membrane-bound Nrf1 transcription factor regulates critical homeostatic and developmental genes. The conserved N-terminal homology box 1 (NHB1) sequence in Nrf1 targets the cap'n'collar (CNC) basic basic-region leucine zipper (bZIP) factor to the endoplasmic reticulum (ER), but it is unknown how its activity is controlled topologically within membranes. Herein, we report a hitherto unknown mechanism by which the transactivation activity of Nrf1 is controlled through its membrane-topology. Thus after Nrf1 is anchored within ER membranes, its acidic transactivation domains (TADs), including the Asn/Ser/Thr-rich (NST) glycodomain situated between acidic domain 1 (AD1) and AD2, are transiently translocated into the lumen of the ER, where NST is glycosylated in the presence of glucose to yield an inactive 120-kDa Nrf1 glycoprotein. Subsequently, portions of the TADs partially repartition across membranes into the cyto/nucleoplasmic compartments, whereupon an active 95-kDa form of Nrf1 accumulates, a process that is more obvious in glucose-deprived cells and may involve deglycosylation. The repartitioning of Nrf1 out of membranes is monitored within this protein by its acidic-hydrophobic amphipathic glucose-responsive domains, particularly the Neh5L subdomain within AD1. Therefore, the membrane-topological organization of Nrf1 dictates its post-translational modifications (i.e. glycosylation, the putative deglycosylation and selective proteolysis), which together control its ability to transactivate target genes.

| S-EPMC3973704 | biostudies-literature

Cytomegalovirus late transcription factor target sequence diversity orchestrates viral early to late transcription.

Project description:Beta- and gammaherpesviruses late transcription factors (LTFs) target viral promoters containing a TATT sequence to drive transcription after viral DNA replication has begun. Human cytomegalovirus (HCMV), a betaherpesvirus, uses the UL87 LTF to bind both TATT and host RNA polymerase II (Pol II), whereas the UL79 LTF has been suggested to drive productive elongation. Here we apply integrated functional genomics (dTag system, PRO-Seq, ChIP-Seq, and promoter function assays) to uncover the contribution of diversity in LTF target sequences in determining degree and scope to which LTFs drive viral transcription. We characterize the DNA sequence patterns in LTF-responsive and -unresponsive promoter populations, determine where and when Pol II initiates transcription, identify sites of LTF binding genome-wide, and quantify change in nascent transcripts from individual promoters in relation to core promoter sequences, LTF loss, stage of infection, and viral DNA replication. We find that HCMV UL79 and UL87 LTFs function concordantly to initiate transcription from over half of all active viral promoters in late infection, while not appreciably affecting host transcription. Both LTFs act on and bind to viral early-late and late kinetic-class promoters. Over one-third of these core promoters lack the TATT and instead have a TATAT, TGTT, or YRYT. The TATT and non-TATT motifs are part of a sequence block with a sequence code that correlates with promoter transcription level. LTF occupancy of a TATATA palindrome shared by back-to-back promoters is linked to bidirectional transcription. We conclude that diversity in LTF target sequences shapes the LTF-transformative program that drives the viral early-to-late transcription switch.

| S-EPMC8360532 | biostudies-literature

Gene expression profile in the tethered Nrf1-MafG (T-N1G) heterodimer-expressing small Maf-deficient cells [RNA-seq]

Project description:Gene expression profile in the tethered Nrf1-MafG (T-N1G) heterodimer-expressing small Maf-deficient cells [RNA-seq]

| PRJNA780313 | ENA

Inhibition of NGLY1 Inactivates the Transcription Factor Nrf1 and Potentiates Proteasome Inhibitor Cytotoxicity.

Project description:Proteasome inhibitors are used to treat blood cancers such as multiple myeloma (MM) and mantle cell lymphoma. The efficacy of these drugs is frequently undermined by acquired resistance. One mechanism of proteasome inhibitor resistance may involve the transcription factor Nuclear Factor, Erythroid 2 Like 1 (NFE2L1, also referred to as Nrf1), which responds to proteasome insufficiency or pharmacological inhibition by upregulating proteasome subunit gene expression. This "bounce-back" response is achieved through a unique mechanism. Nrf1 is constitutively translocated into the ER lumen, N-glycosylated, and then targeted for proteasomal degradation via the ER-associated degradation (ERAD) pathway. Proteasome inhibition leads to accumulation of cytosolic Nrf1, which is then processed to form the active transcription factor. Here we show that the cytosolic enzyme N-glycanase 1 (NGLY1, the human PNGase) is essential for Nrf1 activation in response to proteasome inhibition. Chemical or genetic disruption of NGLY1 activity results in the accumulation of misprocessed Nrf1 that is largely excluded from the nucleus. Under these conditions, Nrf1 is inactive in regulating proteasome subunit gene expression in response to proteasome inhibition. Through a small molecule screen, we identified a cell-active NGLY1 inhibitor that disrupts the processing and function of Nrf1. The compound potentiates the cytotoxicity of carfilzomib, a clinically used proteasome inhibitor, against MM and T cell-derived acute lymphoblastic leukemia (T-ALL) cell lines. Thus, NGLY1 inhibition prevents Nrf1 activation and represents a new therapeutic approach for cancers that depend on proteasome homeostasis.

| S-EPMC5704294 | biostudies-literature

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