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Cited by 20Alzheimer's disease research and treatmentsGenomics and Chromatin DynamicsDementia and Cognitive Impairment Research

Identification of a Nuclear Respiratory Factor 1 Recognition Motif in the Apolipoprotein E Variant APOE4 linked to Alzheimer’s Disease

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Urfer-Buchwalder, Anne, Urfer, Roman·2017·Scientific Reports
DOI 10.1038/srep40668PMC PMC5240558
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Abstract

Alzheimer’s disease affects tens of millions of people worldwide and its prevalence continues to rise. It is caused by a combination of a subject’s heredity, environment, lifestyle, and medical condition. The most significant genetic risk factor for late onset Alzheimer’s disease is a variant of the apolipoprotein E gene, APOE4. Here we show that the single nucleotide polymorphism rs429358 that defines APOE4 is located in a short sequence motif repeated several times within exon 4 of apolipoprotein E, reminiscent of the structure of transcriptional enhancers. A JASPAR database search predicts that the T to C transition in rs429358 generates a binding motif for nuclear respiratory factor NRF1. This site appears to be part of a binding site cluster for this transcription factor on exon 4 of APOE. This de novo NRF1 binding site has therefore the potential to affect the expression of multiple genes in its genomic vicinity. Our in silico analysis, suggesting a novel function for APOE4 at the DNA level, offers a potential mechanism for the observed tissue specific neurodegeneration and the role of environmental factors in Alzheimer’s disease etiology.

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  • ApoE4 modulates action of NRF1, possibly because SNP generates binding motif for NRF1 that underlies ability of ApoE4 to act as transcription factor itself.

    “ApoE4 also modulates the action of another transcription factor, nuclear respiratory factor 1 (NRF1), possibly because the single nucleotide polymorphism generates a binding motif for NRF1 that underlies the ability of ApoE4 to act as a transcription factor itself [78].”

    From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [78]

    The Results section predicts that the APOE4 SNP creates an NRF1-binding motif, and the Discussion suggests that this DNA site could affect nearby gene expression. The paper does not show that APOE4 modulates NRF1 activity or that the ApoE4 protein acts as a transcription factor itself; its proposed mechanism concerns an enhancer-like DNA sequence. (LLM, conf=0.89)

    Experimental — accuracy not yet measured

  • Several of the transcription factors identified are implicated in neurodegeneration, including nuclear respiratory factor 1, nuclear factor erythroid-2-like 2, ETS domain-containing protein Elk-1, Kruppel-like factor 14, and Sp4.

    “Additionally, several of the transcription factors identified are implicated in neurodegeneration, including nuclear respiratory factor 1 [117, 118], nuclear factor erythroid-2-like 2 [110, 111], ETS domain-containing protein Elk-1 [119], Kruppel-like factor 14 [120], and Sp4 [121].”

    From Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function (2019) · cites this paper as [118]

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Research works printed but not linked: 41

  1. Eichner J. E., Dunn S. T., Perveen G., Thompson D. M., Stewart K. E. & Stroehla B. C. Apolipoprotein E polymorphism and cardiovascular disease: A HuGE review. Am J Epidemiol 155, 487– 495 (2002). 11882522
  2. Mahley R. W. & Rall S. C. Jr. Apolipoprotein E: far more than a lipid transport protein. Annu Rev Genomics Hum Genet 1, 507– 37 (2000). 11701639
  3. Zannis V. I., Just P. W. & Breslow J. L. Human apolipoprotein E isoprotein subclasses are genetically determined. Am J Hum Genet 33, 11– 24 (1981). 7468588 PMC1684875
  4. Weisgraber K. H., Rall S. C. & Mahley R. W. Human E apoprotein heterogeneity. Cysteine-arginine interchanges in the amino acid sequence of the apo-E isoforms. J Biol Chem 256, 9077– 9083 (1981). 7263700
  5. Fullerton S. M.. Apolipoprotein E variation at the sequence haplotype level: implications for the origin and maintenance of a major human polymorphism. Am J Hum Genet. 67, 881– 900 (2000). 10986041 PMC1287893
  6. Strittmatter W. J.. Apolipoprotein E: high avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer’s disease. Proc. Natl. Acad. Sci. USA 90, 1977– 81 (1993). 8446617 PMC46003
  7. Saunders A. M.. Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer’s disease. Neurology 43, 1467– 72 (1993). 8350998
  8. Corder E. H.. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261, 921– 923 (1993). 8346443
  9. Lambert J. C.. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet 45, 1452– 8 (2013). 24162737 PMC3896259
  10. Farrer L. A.. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA 278, 1349– 56 (1997). 9343467
  11. Ward A.. Prevalence of apolipoprotein E4 genotype and homozygotes (APOE e4/4) among patients diagnosed with Alzheimer’s disease: a systematic review and meta-analysis. Neuroepidemiology 38, 1– 17 (2012). 22179327
  12. Gatz M.. Role of genes and environments for explaining Alzheimer disease. Arch Gen Psychiatry 63, 168– 74 (2006). 16461860
  13. Genin E.. APOE and Alzheimer disease: a major gene with semi-dominant inheritance. Mol Psychiatry 16, 903– 7 (2011). 21556001 PMC3162068
  14. Xu Q., Bernardo A., Walker D., Kanegawa T., Mahley R. W. & Huang Y. Profile and regulation of apolipoprotein E (ApoE) expression in the CNS in mice with targeting of green fluorescent protein gene to the ApoE locus. J Neurosci 26, 4985– 94 (2006). 16687490 PMC6674234
  15. Grehan S., Tse E. & Taylor J. M. Two distal downstream enhancers direct expression of the human apolipoprotein E gene to astrocytes in the brain. J Neurosci 21, 812– 22 (2001). 11157067 PMC6762321
  16. Aoki K.. Increased expression of neuronal apolipoprotein E in human brain with cerebral infarction. Stroke 34, 875– 80 (2003). 12649507
  17. Sun Y.. Glial fibrillary acidic protein-apolipoprotein E (apoE) transgenic mice: astrocyte-specific expression and differing biological effects of astrocyte-secreted apoE3 and apoE4 lipoproteins. J Neurosci 18, 3261– 72 (1998). 9547235 PMC6792658
  18. Smith J. D., Sikes J. & Levin J. A. Human apolipoprotein E allele-specific brain expressing transgenic mice. Neurobiol Aging 19, 407– 13 (1998). 9880043
  19. Knouff C.. Apo E structure determines VLDL clearance and atherosclerosis risk in mice. J Clin Invest 103, 1579– 86 (1999). 10359567 PMC408371
  20. Medway C. W.. Apoe variant p.V236E is associated with markedly reduced risk of Alzheimer’s disease. Mol Neurodegen 9, 11 (2014). PMC3995879 24607147
  21. Yu C. E.. Epigenetic signature and enhancer activity of the human APOE gene. Hum Mol Genet 22, 5036– 47 (2013). 23892237 PMC3836480
  22. Chen H. P.. Screening reveals conserved and nonconserved transcriptional regulatory elements including an E3/E4 allele-dependent APOE coding region enhancer. Genomics 92, 292– 300 (2008). 18718521
  23. Dynan W. S. Modularity in promoters and enhancers. Cell 58, 1– 4 (1989). 2665940
  24. Rao S. S.. A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Cell 159, 1665– 80 (2014). 25497547 PMC5635824
  25. Guenther C. A., Tasic B., Luo L., Bedell M. A. & Kingsley D. M. A molecular basis for classic blond hair color in Europeans. Nat Genet 46, 748– 52 (2014). 24880339 PMC4704868
  26. Maas S. A. & Fallon J. F. Single base pair change in the long-range Sonic hedgehog limb-specific enhancer is a genetic basis for preaxial polydactyly. Dev Dyn 232, 345– 8 (2005). 15637698
  27. Wang X.. A Polymorphic Antioxidant Response Element Links NRF2/sMAF Binding to Enhanced MAPT Expression and Reduced Risk of Parkinsonian Disorders. Cell Reports 15, 830– 842 (2016). PMC5063658 27149848
  28. Soldner F.. Parkinson-associated risk variant in distal enhancer of α-synuclein modulates target gene expression. Nature 533, 95– 9 (2016). 27096366 PMC5042324
  29. Kelly D. P. & Scarpulla R. C. Transcriptional regulatory circuits controlling mitochondrial biogenesis and function. Genes Dev 18, 357– 68 (2004). 15004004
  30. Johar K., Priya A. & Wong-Riley M. T. Regulation of Na(+)/K(+)-ATPase by nuclear respiratory factor 1: implication in the tight coupling of neuronal activity, energy generation, and energy consumption. J Biol Chem 287, 40381– 90 (2012). 23048038 PMC3504753
  31. Chang W. T., Chen H. I., Chiou R. J., Chen C. Y. & Huang A. M. A novel function of transcription factor alpha-Pal/NRF-1: increasing neurite outgrowth. Biochem Biophys Res Commun 334, 199– 206 (2005). 15992771
  32. Choi Y. S., Lee K. U. & Pak Y. K. Regulation of mitochondrial transcription factor A expression by high glucose. Ann N Y Acad Sci 1011, 69– 77 (2004). 15126285
  33. Piantadosi C. A. & Suliman H. B. Mitochondrial transcription factor A induction by redox activation of nuclear respiratory factor 1. J Biol Chem 281, 324– 33 (2006). 16230352
  34. Tokusumi Y., Zhou S. & Takada S. Nuclear respiratory factor 1 plays an essential role in transcriptional initiation from the hepatitis B virus x gene promoter. J Virol 78, 10856– 64 (2004). 15452206 PMC521811
  35. Lezza A. M.. Increased expression of mitochondrial transcription factor A and nuclear respiratory factor-1 in skeletal muscle from aged human subjects. FEBS Lett 501, 74– 8 (2001). 11457459
  36. Chandrasekaran S. & Bonchev D. Network Topology Analysis of Post-Mortem Brain Microarrays Identifies More Alzheimer’s Related Genes and MicroRNAs and Points to Novel Routes for Fighting with the Disease. PLoS One 11, e0144052 (2016). Erratum in: PLoS One 11, e0151122 (2016). 26784894 PMC4718516
  37. Satoh J., Kawana N. & Yamamoto Y. Pathway Analysis of ChIP-Seq-Based NRF1 Target Genes Suggests a Logical Hypothesis of their Involvement in the Pathogenesis of Neurodegenerative Diseases. Gene Regul Syst Bio 7, 139– 52 (2013). PMC3825669 24250222
  38. Mathelier A.. JASPAR 2014: an extensively expanded and updated open-access database of transcription factor binding profiles. Nucleic Acids Res 42, D142– D147 (2014). 24194598 PMC3965086
  39. van den Hoven R.. Putative regulation mechanism for the MSTN gene by a CpG island generated by the SINE marker Ins227bp. BMC Vet Res 11, 138 (2015). 26100061 PMC4476204
  40. Benítez-Bellón E., Moreno-Hagelsieb G. & Collado-Vides J. Evaluation of thresholds for the detection of binding sites for regulatory proteins in Escherichia coli K12 DNA. Genome Biol 3, RESEARCH0013 (2002). PMC88811 11897025
  41. Schneider D. T. & Stephens R. M. Sequence logos: a new way to display consensus sequences. Nucleic Acids Research 18, 6097– 6100 (1990). 2172928 PMC332411

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Authors
Urfer-Buchwalder, A., & Urfer, R.
Corresponding author
Urfer-Buchwalder, Anne
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2017-01-17
Volume
7
Issue
1
Pages
40668-40668
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/srep40668
PMC
PMC5240558
OpenAlex
W2579712787
Cited by
20
References
5
Citations by year
2026: 1 · 2024: 2 · 2023: 5 · 2022: 2 · 2021: 1 · 2020: 1 · 2019: 4 · 2018: 2 · 2017: 2
FWCI
1.75
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, APOE ε4, apolipoprotein E, NRF1, transcription factor binding sites, rs429358, single nucleotide polymorphisms, enhancers, exon 4, genetic risk factors, late-onset Alzheimer's disease
MeSH terms
Alleles, Alzheimer Disease, Base Sequence, Binding Sites, Exons, Gene Expression Regulation, Humans, Protein Binding, Genetic Variation, Polymorphism, Single Nucleotide, Nuclear Respiratory Factor 1, Apolipoprotein E4, Position-Specific Scoring Matrices, Nucleotide Motifs

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