Genetic determinants of neuroglobin transcription

R. Wang, E. Halper-Stromberg, M. Szymanski-Pierce, Susan Bassett, Dimitrios Avramopoulos

Research output: Contribution to journalArticle

Abstract

Neuroglobin (NGB) is a neuron-specific vertebrate globin shown to protect against hypoxia, ischemia, oxidative stress and the toxic effects of Amyloid-beta. Following on our and others' results highlighting the importance of NGB expression in disease, we searched for genetic determinants of its expression. We found that a microRNA expressed with the NGB transcript shows significant target enrichments in the angiogenesis pathway and the Alzheimer disease/presenilin pathway. Using reporter constructs we identified potential promoter/enhancer elements between the transcription start site and 1,142 bp upstream. Using 184 post-mortem temporal lobe samples we replicated the reported negative effect of age, and after genotyping tagging SNPs we found one (rs981471) showing a significant correlation with the gene's expression and another (rs8014408) showing an interaction with age, the rare C allele being correlated with higher expression and faster decline. The two SNPs are towards the 3 end of NGB within the same LD block, 52 Kb apart and modestly correlated (r 2∈=∈0.5). Next generation sequencing of the same 184 temporal lobe samples and 79 confirmed AD patients across the entire gene region (including >12 Kb on the 3 and 5 flank) revealed limited coding variation, suggesting purifying selection of NGB, but did not identify regulatory or disease associated rare variants. A dinucleotide repeat in intron 1 with extensive evidence of functionality showed interesting but inconclusive results, as it was not amenable to further molecular analysis.

Original languageEnglish (US)
Pages (from-to)65-75
Number of pages11
JournalNeurogenetics
Volume15
Issue number1
DOIs
StatePublished - 2014

Fingerprint

Temporal Lobe
Single Nucleotide Polymorphism
Presenilins
Dinucleotide Repeats
Inborn Genetic Diseases
Globins
Poisons
Transcription Initiation Site
Rare Diseases
MicroRNAs
Amyloid
Introns
Vertebrates
Alzheimer Disease
Oxidative Stress
Ischemia
Alleles
neuroglobin
Gene Expression
Neurons

Keywords

  • Alzheimer's disease
  • Gene expression
  • Genetics
  • Neuroglobin
  • Polymorphism
  • Promoter
  • Stroke
  • Transcription

ASJC Scopus subject areas

  • Genetics(clinical)
  • Cellular and Molecular Neuroscience
  • Genetics

Cite this

Genetic determinants of neuroglobin transcription. / Wang, R.; Halper-Stromberg, E.; Szymanski-Pierce, M.; Bassett, Susan; Avramopoulos, Dimitrios.

In: Neurogenetics, Vol. 15, No. 1, 2014, p. 65-75.

Research output: Contribution to journalArticle

Wang, R, Halper-Stromberg, E, Szymanski-Pierce, M, Bassett, S & Avramopoulos, D 2014, 'Genetic determinants of neuroglobin transcription', Neurogenetics, vol. 15, no. 1, pp. 65-75. https://doi.org/10.1007/s10048-013-0388-3
Wang, R. ; Halper-Stromberg, E. ; Szymanski-Pierce, M. ; Bassett, Susan ; Avramopoulos, Dimitrios. / Genetic determinants of neuroglobin transcription. In: Neurogenetics. 2014 ; Vol. 15, No. 1. pp. 65-75.
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