* 600879

NUCLEAR RESPIRATORY FACTOR 1; NRF1


Alternative titles; symbols

ALPHA-PAL


HGNC Approved Gene Symbol: NRF1

Cytogenetic location: 7q32.2     Genomic coordinates (GRCh38): 7:129,611,720-129,757,076 (from NCBI)


TEXT

Description

Gopalakrishnan and Scarpulla (1995) noted that the electron transport chain and oxidative phosphorylation system rely on the functional interplay of gene products expressed from both nuclear and mitochondrial genomes. Because of the limited coding capacity of the mitochondrial chromosome, nuclear genes must provide most of the respiratory subunits and all of the gene products necessary for mitochondrial DNA transcription and replication. Nuclear respiratory factor-1 (NRF1) is a transcription factor that acts on nuclear genes encoding respiratory subunits and components of the mitochondrial transcription and replication machinery.


Cloning and Expression

Virbasius et al. (1993) cloned the human NRF1 cDNA from HeLa cells using degenerate primers based on partial tryptic peptide sequences and showed a predicted 504 amino acid protein encoded by a 2,970 nucleotide cDNA. The recombinantly expressed protein activated transcription of several NRF1-responsive promoters.

The NRF1 transcription factor binds to 2 palindromic sites within the promoter of the eIF-2-alpha (603907) gene and is essential for eIF-2-alpha transcription. Efiok et al. (1994) cloned human cDNAs encoding NRF1, which they called alpha-Pal. Sequence analysis indicated that alpha-Pal is a putative bZIP transcription factor with strong homology to sea urchin P3A2 and Drosophila ewg, developmental transcription factors. Northern blot analysis revealed that alpha-Pal was expressed as 2.4- and 3.4-kb mRNAs in all human tissues tested, with the strongest expression in skeletal muscle.

In studies of the expression of the NRF1 gene in cultured human fibroblasts, Spelbrink and Van den Bogert (1995) identified 2 distinct NRF1 transcripts using RT-PCR, 1 of which contained an in-frame deletion of 198 bp. Sequencing of genomic DNA showed that the shorter mRNA is the result of alternative splicing, with exon skipping. The shorter transcript was predicted to result in an isoform of the protein that lacks the carboxy-terminal part of the DNA binding domain, which they speculated might influence transcriptional activation by normal nuclear respiratory factor 1. The alternatively spliced transcript was also present in other human cell lines and in several human tissues. A quantitative PCR analysis showed that the percentages of the alternatively spliced transcript ranged from 3 to 17%. The authors further speculated that differences in the percentage of alternatively spliced NRF1 pre-mRNA may influence mitochondrial biogenesis under variable physiologic conditions and may play a role in distinct mitochondrial diseases.


Gene Function

Efiok et al. (1994) identified genes containing alpha-Pal-binding sequences and found that these could be classified either as cellular proliferation genes, or as genes regulating the growth-responsive metabolic pathways of energy transduction, translation, and replication. The authors proposed that alpha-Pal is a transcription factor that links the transcriptional modulation of key metabolic genes to cellular growth and development.

Virbasius and Scarpulla (1994) noted that the nuclear-encoded mitochondrial transcription factor TFAM (600438) contains potential binding sites for NRF1, NRF2 (GABPA; 600609) and SP1 (189906) within the promoter region. With use of binding and electrophoretic mobility shift assays, DNase footprinting, and mutation analysis of recombinant proteins, they demonstrated specific and functional binding of NRF1 and NRF2 to the TFAM promoter region. Methylation of the guanine nucleotides in the tandem GCGC motifs interfered with NRF1 binding. With use of reporter constructs and mutation analysis, they determined that NRF1 has a more robust effect on TFAM promoter activity than NRF2 or SP1. Further, activation by NRF2 or SP1 required the presence of a functional NRF1-binding site.

Wang et al. (2006) found that mouse cyclin D1 (CCND1; 168461) repressed the expression and activity of Nrf1 via phosphorylation at ser47.

To explore the contribution of DNA methylation to constrained transcription factor binding, Domcke et al. (2015) mapped DNase-I-hypersensitive sites in murine stem cells in the presence and absence of DNA methylation. Methylation-restricted sites are enriched for transcription factor motifs containing CpGs, especially for those of NRF1. In fact, the transcription factor NRF1 occupies several thousand additional sites in the unmethylated genome, resulting in increased transcription. Restoring de novo methyltransferase activity initiates remethylation at these sites and outcompetes NRF1 binding. This suggests that binding of DNA methylation-sensitive transcription factors relies on additional determinants to induce local hypomethylation. In support of this model, removal of neighboring motifs in cis or of a transcription factor in trans causes local hypermethylation and subsequent loss of NRF1 binding. This competition between DNA methylation and transcription factors in vivo reveals a case of cooperativity between transcription factors that acts indirectly via DNA methylation. Methylation removal by methylation-insensitive factors enables occupancy of methylation-sensitive factors, a principle that rationalizes hypomethylation of regulatory regions.


Gene Structure

Gopalakrishnan and Scarpulla (1995) isolated and characterized the human gene encoding NRF1. The NRF1 gene spans approximately 65 kb and has 11 exons and 10 introns that range in size from 0.8 to 15 kb. The authors noted that these analyses should be useful in evaluating the potential role of NRF1 in mitochondrial diseases resulting from defects in the nuclear control of mitochondrial function.


Mapping

Gopalakrishnan and Scarpulla (1995) analyzed DNA from a panel of human/hamster cell hybrids using human-specific NRF1 PCR primers and localized the NRF1 gene to human chromosome 7. The assignment was further refined to 7q31 by cohybridization of NRF1- and chromosome 7-specific probes to human metaphase chromosomes. Tiranti et al. (1995) mapped the NRF1 gene to 7q32 by fluorescence in situ hybridization. (They referred to the gene as NFE2L1; this symbol had already been reserved for the NF-E2-related factor 1 (163260).)


REFERENCES

  1. Domcke, S., Bardet, A. F., Ginno, P. A., Hartl, D., Burger, L., Schubeler, D. Competition between DNA methylation and transcription factors determines binding of NRF1. Nature 528: 575-579, 2015. [PubMed: 26675734, related citations] [Full Text]

  2. Efiok, B. J. S., Chiorini, J. A., Safer, B. A key transcription factor for eukaryotic initiation factor-2-alpha is strongly homologous to developmental transcription factors and may link metabolic genes to cellular growth and development. J. Biol. Chem. 269: 18921-18930, 1994. [PubMed: 8034649, related citations]

  3. Gopalakrishnan, L., Scarpulla, R. C. Structure, expression, and chromosomal assignment of the human gene encoding nuclear respiratory factor 1. J. Biol. Chem. 270: 18019-18025, 1995. [PubMed: 7629110, related citations] [Full Text]

  4. Spelbrink, J. N., Van den Bogert, C. The pre-mRNA of nuclear respiratory factor 1, a regulator of mitochondrial biogenesis, is alternatively spliced in human tissues and cell lines. Hum. Molec. Genet. 4: 1591-1596, 1995. [PubMed: 8541844, related citations] [Full Text]

  5. Tiranti, V., Rossi, E., Rocchi, M., DiDonato, S., Zuffardi, O., Zeviani, M. The gene (NFE2L1) for human NRF-1, an activator involved in nuclear-mitochondrial interactions, maps to 7q32. Genomics 27: 555-557, 1995. [PubMed: 7558044, related citations] [Full Text]

  6. Virbasius, C. A., Virbasius, J. V., Scarpulla, R. C. NRF-1, an activator involved in nuclear-mitochondrial interactions, utilizes a new DNA-binding domain conserved in a family of developmental regulators. Genes Dev. 7: 2431-2445, 1993. [PubMed: 8253388, related citations] [Full Text]

  7. Virbasius, J. V., Scarpulla, R. C. Activation of the human mitochondrial transcription factor A gene by nuclear respiratory factors: a potential regulatory link between nuclear and mitochondrial gene expression in organelle biogenesis. Proc. Nat. Acad. Sci. 91: 1309-1313, 1994. [PubMed: 8108407, related citations] [Full Text]

  8. Wang, C., Li, Z., Lu, Y., Du, R., Katiyar, S., Yang, J., Fu, M., Leader, J. E., Quong, A., Novikoff, P. M., Pestell, R. G. Cyclin D1 repression of nuclear respiratory factor 1 integrates nuclear DNA synthesis and mitochondrial function. Proc. Nat. Acad. Sci. 103: 11567-11572, 2006. [PubMed: 16864783, images, related citations] [Full Text]


Ada Hamosh - updated : 12/06/2016
Patricia A. Hartz - updated : 10/3/2006
Patricia A. Hartz - updated : 6/28/2002
Rebekah S. Rasooly - updated : 6/17/1999
Alan F. Scott - updated : 3/27/1996
Creation Date:
Victor A. McKusick : 10/19/1995
alopez : 12/06/2016
mgross : 10/09/2006
terry : 10/3/2006
carol : 6/28/2002
alopez : 6/17/1999
alopez : 6/17/1999
mgross : 3/15/1999
terry : 6/4/1998
terry : 4/17/1996
mark : 3/27/1996
mark : 10/19/1995

* 600879

NUCLEAR RESPIRATORY FACTOR 1; NRF1


Alternative titles; symbols

ALPHA-PAL


HGNC Approved Gene Symbol: NRF1

Cytogenetic location: 7q32.2     Genomic coordinates (GRCh38): 7:129,611,720-129,757,076 (from NCBI)


TEXT

Description

Gopalakrishnan and Scarpulla (1995) noted that the electron transport chain and oxidative phosphorylation system rely on the functional interplay of gene products expressed from both nuclear and mitochondrial genomes. Because of the limited coding capacity of the mitochondrial chromosome, nuclear genes must provide most of the respiratory subunits and all of the gene products necessary for mitochondrial DNA transcription and replication. Nuclear respiratory factor-1 (NRF1) is a transcription factor that acts on nuclear genes encoding respiratory subunits and components of the mitochondrial transcription and replication machinery.


Cloning and Expression

Virbasius et al. (1993) cloned the human NRF1 cDNA from HeLa cells using degenerate primers based on partial tryptic peptide sequences and showed a predicted 504 amino acid protein encoded by a 2,970 nucleotide cDNA. The recombinantly expressed protein activated transcription of several NRF1-responsive promoters.

The NRF1 transcription factor binds to 2 palindromic sites within the promoter of the eIF-2-alpha (603907) gene and is essential for eIF-2-alpha transcription. Efiok et al. (1994) cloned human cDNAs encoding NRF1, which they called alpha-Pal. Sequence analysis indicated that alpha-Pal is a putative bZIP transcription factor with strong homology to sea urchin P3A2 and Drosophila ewg, developmental transcription factors. Northern blot analysis revealed that alpha-Pal was expressed as 2.4- and 3.4-kb mRNAs in all human tissues tested, with the strongest expression in skeletal muscle.

In studies of the expression of the NRF1 gene in cultured human fibroblasts, Spelbrink and Van den Bogert (1995) identified 2 distinct NRF1 transcripts using RT-PCR, 1 of which contained an in-frame deletion of 198 bp. Sequencing of genomic DNA showed that the shorter mRNA is the result of alternative splicing, with exon skipping. The shorter transcript was predicted to result in an isoform of the protein that lacks the carboxy-terminal part of the DNA binding domain, which they speculated might influence transcriptional activation by normal nuclear respiratory factor 1. The alternatively spliced transcript was also present in other human cell lines and in several human tissues. A quantitative PCR analysis showed that the percentages of the alternatively spliced transcript ranged from 3 to 17%. The authors further speculated that differences in the percentage of alternatively spliced NRF1 pre-mRNA may influence mitochondrial biogenesis under variable physiologic conditions and may play a role in distinct mitochondrial diseases.


Gene Function

Efiok et al. (1994) identified genes containing alpha-Pal-binding sequences and found that these could be classified either as cellular proliferation genes, or as genes regulating the growth-responsive metabolic pathways of energy transduction, translation, and replication. The authors proposed that alpha-Pal is a transcription factor that links the transcriptional modulation of key metabolic genes to cellular growth and development.

Virbasius and Scarpulla (1994) noted that the nuclear-encoded mitochondrial transcription factor TFAM (600438) contains potential binding sites for NRF1, NRF2 (GABPA; 600609) and SP1 (189906) within the promoter region. With use of binding and electrophoretic mobility shift assays, DNase footprinting, and mutation analysis of recombinant proteins, they demonstrated specific and functional binding of NRF1 and NRF2 to the TFAM promoter region. Methylation of the guanine nucleotides in the tandem GCGC motifs interfered with NRF1 binding. With use of reporter constructs and mutation analysis, they determined that NRF1 has a more robust effect on TFAM promoter activity than NRF2 or SP1. Further, activation by NRF2 or SP1 required the presence of a functional NRF1-binding site.

Wang et al. (2006) found that mouse cyclin D1 (CCND1; 168461) repressed the expression and activity of Nrf1 via phosphorylation at ser47.

To explore the contribution of DNA methylation to constrained transcription factor binding, Domcke et al. (2015) mapped DNase-I-hypersensitive sites in murine stem cells in the presence and absence of DNA methylation. Methylation-restricted sites are enriched for transcription factor motifs containing CpGs, especially for those of NRF1. In fact, the transcription factor NRF1 occupies several thousand additional sites in the unmethylated genome, resulting in increased transcription. Restoring de novo methyltransferase activity initiates remethylation at these sites and outcompetes NRF1 binding. This suggests that binding of DNA methylation-sensitive transcription factors relies on additional determinants to induce local hypomethylation. In support of this model, removal of neighboring motifs in cis or of a transcription factor in trans causes local hypermethylation and subsequent loss of NRF1 binding. This competition between DNA methylation and transcription factors in vivo reveals a case of cooperativity between transcription factors that acts indirectly via DNA methylation. Methylation removal by methylation-insensitive factors enables occupancy of methylation-sensitive factors, a principle that rationalizes hypomethylation of regulatory regions.


Gene Structure

Gopalakrishnan and Scarpulla (1995) isolated and characterized the human gene encoding NRF1. The NRF1 gene spans approximately 65 kb and has 11 exons and 10 introns that range in size from 0.8 to 15 kb. The authors noted that these analyses should be useful in evaluating the potential role of NRF1 in mitochondrial diseases resulting from defects in the nuclear control of mitochondrial function.


Mapping

Gopalakrishnan and Scarpulla (1995) analyzed DNA from a panel of human/hamster cell hybrids using human-specific NRF1 PCR primers and localized the NRF1 gene to human chromosome 7. The assignment was further refined to 7q31 by cohybridization of NRF1- and chromosome 7-specific probes to human metaphase chromosomes. Tiranti et al. (1995) mapped the NRF1 gene to 7q32 by fluorescence in situ hybridization. (They referred to the gene as NFE2L1; this symbol had already been reserved for the NF-E2-related factor 1 (163260).)


REFERENCES

  1. Domcke, S., Bardet, A. F., Ginno, P. A., Hartl, D., Burger, L., Schubeler, D. Competition between DNA methylation and transcription factors determines binding of NRF1. Nature 528: 575-579, 2015. [PubMed: 26675734] [Full Text: https://doi.org/10.1038/nature16462]

  2. Efiok, B. J. S., Chiorini, J. A., Safer, B. A key transcription factor for eukaryotic initiation factor-2-alpha is strongly homologous to developmental transcription factors and may link metabolic genes to cellular growth and development. J. Biol. Chem. 269: 18921-18930, 1994. [PubMed: 8034649]

  3. Gopalakrishnan, L., Scarpulla, R. C. Structure, expression, and chromosomal assignment of the human gene encoding nuclear respiratory factor 1. J. Biol. Chem. 270: 18019-18025, 1995. [PubMed: 7629110] [Full Text: https://doi.org/10.1074/jbc.270.30.18019]

  4. Spelbrink, J. N., Van den Bogert, C. The pre-mRNA of nuclear respiratory factor 1, a regulator of mitochondrial biogenesis, is alternatively spliced in human tissues and cell lines. Hum. Molec. Genet. 4: 1591-1596, 1995. [PubMed: 8541844] [Full Text: https://doi.org/10.1093/hmg/4.9.1591]

  5. Tiranti, V., Rossi, E., Rocchi, M., DiDonato, S., Zuffardi, O., Zeviani, M. The gene (NFE2L1) for human NRF-1, an activator involved in nuclear-mitochondrial interactions, maps to 7q32. Genomics 27: 555-557, 1995. [PubMed: 7558044] [Full Text: https://doi.org/10.1006/geno.1995.1094]

  6. Virbasius, C. A., Virbasius, J. V., Scarpulla, R. C. NRF-1, an activator involved in nuclear-mitochondrial interactions, utilizes a new DNA-binding domain conserved in a family of developmental regulators. Genes Dev. 7: 2431-2445, 1993. [PubMed: 8253388] [Full Text: https://doi.org/10.1101/gad.7.12a.2431]

  7. Virbasius, J. V., Scarpulla, R. C. Activation of the human mitochondrial transcription factor A gene by nuclear respiratory factors: a potential regulatory link between nuclear and mitochondrial gene expression in organelle biogenesis. Proc. Nat. Acad. Sci. 91: 1309-1313, 1994. [PubMed: 8108407] [Full Text: https://doi.org/10.1073/pnas.91.4.1309]

  8. Wang, C., Li, Z., Lu, Y., Du, R., Katiyar, S., Yang, J., Fu, M., Leader, J. E., Quong, A., Novikoff, P. M., Pestell, R. G. Cyclin D1 repression of nuclear respiratory factor 1 integrates nuclear DNA synthesis and mitochondrial function. Proc. Nat. Acad. Sci. 103: 11567-11572, 2006. [PubMed: 16864783] [Full Text: https://doi.org/10.1073/pnas.0603363103]


Contributors:
Ada Hamosh - updated : 12/06/2016
Patricia A. Hartz - updated : 10/3/2006
Patricia A. Hartz - updated : 6/28/2002
Rebekah S. Rasooly - updated : 6/17/1999
Alan F. Scott - updated : 3/27/1996

Creation Date:
Victor A. McKusick : 10/19/1995

Edit History:
alopez : 12/06/2016
mgross : 10/09/2006
terry : 10/3/2006
carol : 6/28/2002
alopez : 6/17/1999
alopez : 6/17/1999
mgross : 3/15/1999
terry : 6/4/1998
terry : 4/17/1996
mark : 3/27/1996
mark : 10/19/1995