Epigenetic considerations of the APOE gene

Yu, Chang; Foraker, Jessica

doi:10.1515/bmc-2014-0039

Cited by 14 publications

(9 citation statements)

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“…APOE ε4 bears two CG dinucleotides mediated by rs429358 (minor allele) and rs7412 (major allele) that reside in the CpG island of exon 4 (Fig. 5 ) [ 18 , 28 ]. rs769450 does not affect CG content (Table 2 ), while rs440446, the first target haplotype SNP meditates the CG dinucleotide arisen by minor allele, similar to the last ones,.…”

Section: Resultsmentioning

confidence: 99%

“…Its relatively rapid expansion could be attributed to converging to meat diet in ancient human populations [ 30 ]. The data suggest also that specific APOE haplotypes might have protective effect against AD development potentially via epigenetic reprogramming of APOE due to CpG emergence/dropout [ 18 , 28 ]. Altogether, our data demonstrated that ethnic genetic background defines significant differences in haplotypes for AD- risk alleles in human populations that may potentially be additional factor modifying risk for AD.…”

Section: Discussionmentioning

confidence: 99%

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Haplotype analysis of APOE intragenic SNPs

et al. 2018

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BackgroundAPOE ε4 allele is most common genetic risk factor for Alzheimer’s disease (AD) and cognitive decline. However, it remains poorly understood why only some carriers of APOE ε4 develop AD and how ethnic variabilities in APOE locus contribute to AD risk. Here, to address the role of APOE haplotypes, we reassessed the diversity of APOE locus in major ethnic groups and in Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset on patients with AD, and subjects with mild cognitive impairment (MCI), and control non-demented individuals.ResultsWe performed APOE gene haplotype analysis for a short block of five SNPs across the gene using the ADNI whole genome sequencing dataset. The compilation of ADNI data with 1000 Genomes identified the APOE ε4 linked haplotypes, which appeared to be distant for the Asian, African and European populations. The common European ε4-bearing haplotype is associated with AD but not with MCI, and the Africans lack this haplotype. Haplotypic inference revealed alleles that may confer protection against AD. By assessing the DNA methylation profile of the APOE haplotypes, we found that the AD-associated haplotype features elevated APOE CpG content, implying that this locus can also be regulated by genetic-epigenetic interactions.ConclusionsWe showed that SNP frequency profiles within APOE locus are highly skewed to population-specific haplotypes, suggesting that the ancestral background within different sites at APOE gene may shape the disease phenotype. We propose that our results can be utilized for more specific risk assessment based on population descent of the individuals and on higher specificity of five site haplotypes associated with AD.Electronic supplementary materialThe online version of this article (10.1186/s12868-018-0413-4) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Haplotype analysis of APOE intragenic SNPs

et al. 2018

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“…Notably, the two single nucleotide polymorphisms (SNPs) that define the ε2/ε3/ε4 alleles of APOE are both CpG dinucleotide altering, such that the ε4 allele introduces an additional CpG site in an already CpG-dense region (i.e., four CpGs within 12 bp) compared to the ε3 and ε2 alleles. In contrast, the ε2 allele eliminates one CpG site to open up a 33-bp CpG-free region compared to the ε3 and ε4 alleles (Yu and Foraker, 2015). Whether such a difference in the epigenetic code can lead to diverse epigenetic changes and contributes to the differential AD risks associated with the ε2/ε3/ε4 alleles is currently under investigation.…”

Section: Introductionmentioning

confidence: 99%

Glia-specific APOE epigenetic changes in the Alzheimer’s disease brain

et al. 2018

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The apolipoprotein E gene (APOE) is the strongest genetic risk factor or developing Alzheimer’s disease (AD). Our recent identification of altered APOE DNA methylation in AD postmortem brain (PMB) prompted this follow-up study. Our goals were to (i) validate the AD-differential methylation of APOE in an independent PMB study cohort and (ii) determine the cellular populations (i.e., neuronal vs. non-neuronal) of AD PMB that contribute to this differential methylation. Here, we obtained an independent cohort of 57 PMB (42 AD and 15 controls) and quantified their APOE methylation levels from frontal lobe and cerebellar tissue. We also applied fluorescence-activated nuclei sorting (FANS) to separate neuronal nuclei from non-neuronal nuclei within the tissue of 15 AD and 14 control subjects. Bisulfite pyrosequencing was used to generate DNA methylation profiles of APOE from both bulk PMB and FANS nuclei. Our results provide independent validation that the APOE CGI holds lower DNA methylation levels in AD compared to control in frontal lobe but not cerebellar tissue. Our data also indicate that the non-neuronal cells of the AD brain, which are mainly composed of glia, are the main contributor to the lower APOE DNA methylation observed in AD PMB. Given that astrocytes are the primary producers of apoE in the brain our results suggest that alteration of epigenetically regulated APOE expression in glia could be an important part of APOE’s strong effect on AD risk.

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“…Interestingly, the exon 4 region of APOE that encompasses the ε 2/ ε 3/ ε 4 allele variants, is also a well-defined CGI [12]. Furthermore, the two ε 2/ ε 3/ ε 4 allele-defining SNPs (rs429358 and rs7412) are both CpG-altering and amend the CpG content of this CGI.…”

Section: Introductionmentioning

confidence: 99%

The APOE Gene is Differentially Methylated in Alzheimer’s Disease

Foraker

Millard

Leong

et al. 2015

JAD

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The ɛ4 allele of the human apolipoprotein E gene (APOE) is a well-proven genetic risk factor for the late onset form of Alzheimer's disease (AD). However, the biological mechanisms through which the ɛ4 allele contributes to disease pathophysiology are incompletely understood. The three common alleles of APOE, ɛ2, ɛ3 and ɛ4, are defined by two single nucleotide polymorphisms (SNPs) that reside in the coding region of exon 4, which overlaps with a well-defined CpG island (CGI). Both SNPs change not only the protein codon but also the quantity of CpG dinucleotides, primary sites for DNA methylation. Thus, we hypothesize that the presence of an ɛ4 allele changes the DNA methylation landscape of the APOE CGI and that such epigenetic alteration contributes to AD susceptibility. To explore the relationship between APOE genotype, AD risk, and DNA methylation of the APOE CGI, we applied bisulfite pyrosequencing and evaluated methylation profiles of postmortem brain from 15 AD and 10 control subjects. We observed a tissue-specific decrease in DNA methylation with AD and identified two AD-specific differentially methylated regions (DMRs), which were also associated with APOE genotype. We further demonstrated that one DMR was completely un-methylated in a sub-population of genomes, possibly due to a subset of brain cells carrying deviated APOE methylation profiles. These data suggest that the APOE CGI is differentially methylated in AD brain in a tissue- and APOE-genotype-specific manner. Such epigenetic alteration might contribute to neural cell dysfunction in AD brain.

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Epigenetic considerations of the APOE gene

Cited by 14 publications

References 47 publications

Haplotype analysis of APOE intragenic SNPs

Haplotype analysis of APOE intragenic SNPs

Glia-specific APOE epigenetic changes in the Alzheimer’s disease brain

The APOE Gene is Differentially Methylated in Alzheimer’s Disease

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