Alzheimer’s Disease DNA Methylome of Pyramidal Layers in Frontal Cortex: Laser-Assisted Microdissection Study

Hernández, Hernán Guillermo; Sandoval-Hernández, Adrián G.; Garrido‐Gil, Pablo; Labandeira‐Garcia, Jose L.; Zelaya, María Victoria; Bayón, Gustavo F.; Fernández, Agustín F.; Fraga, Mario F.; Arboleda, Gonzálo; Arboleda, Humberto

doi:10.2217/epi-2017-0160

Cited by 28 publications

(26 citation statements)

References 92 publications

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“…This is not surprising given the single genome-wide significant DMP in the HOXA gene cluster and multiple significant DMRs in both HOXA and HOXB gene clusters were identified in this study. Both HOXA and HOXB differential methylation findings were reported previously in the AD brain [17][18][19][20][21]32]. Additionally, HOXA differential methylation was reported in the blood from patients with Down syndrome [33] and HOXB differential methylation was also reported in the blood from patients with AD [34].…”

Section: Discussionsupporting

confidence: 70%

“…Oxidative bisulfite conversion may further distinguish 5-mC from 5-hmC [16]. Epigenome-wide association studies (EWAS) using bisulfite conversion approaches coupled with the Illumina Infinium ® Human-Methylation450 BeadChip have demonstrated robust and reproducible differences in total DNA methylation at a number of loci in AD brain [17][18][19][20][21][22], including ankyrin 1 (ANK1), ABCA7, BIN1, TREM2, and the HOXA and HOXB gene clusters. Notably, a recent meta-analysis using samples from 6 cohorts identified a total of 220 DMPs in a cross-cortex meta-analysis [21].…”

Section: Introductionmentioning

confidence: 99%

“…This is a study using DNA extracted from bulk tissue despite the correction for neuronal proportion in the DMP analysis. Studies on cell-type specific methylation pattern [19,32] revealed cell-type specific effect, which could be obscured in studies using bulk tissues. Finally, this study did not distinguish between 5-mC and 5-hmC and could have missed specific differences between the two.…”

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confidence: 99%

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Epigenome-wide association study of Alzheimer’s disease replicates 22 differentially methylated positions and 30 differentially methylated regions

Sun

Wang

2020

Clin Epigenet

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Background Growing evidence shows that epigenetic modifications play a role in Alzheimer’s disease (AD). We performed an epigenome-wide association study (EWAS) to evaluate the DNA methylation differences using postmortem superior temporal gyrus (STG) and inferior frontal gyrus (IFG) samples. Results Samples from 72 AD patients and 62 age-matched cognitively normal controls were assayed using Illumina© Infinium MethylationEPIC BeadChip. Five and 14 differentially methylated positions (DMPs) associated with pathology (i.e., Braak stage) with p value less than Bonferroni correction threshold of 6.79 × 10–8 in the STG and IFG were identified, respectively. These cytosine–phosphate–guanine (CpG) sites included promoter associated cg26263477 annotated to ABCA7 in the STG (p = 1.21 × 10–11), and cg14058329 annotated to the HOXA5/HOXA3/HOXA-AS3 gene cluster (p = 1.62 × 10–9) and cg09448088 (p = 3.95 × 10–9) annotated to MCF2L in the IFG. These genes were previously reported to harbor DMPs and/or differentially methylated regions (DMRs). Previously reported DMPs annotated to RMGA, GNG7, HOXA3, GPR56, SPG7, PCNT, RP11-961A15.1, MCF2L, RHBDF2, ANK1, PCNT, TPRG1, and RASGEF1C were replicated (p < 0.0001). One hundred twenty-one and 173 DMRs associated with pathology in the STG and IFG, respectively, were additionally identified. Of these, DMRs annotated to 30 unique genes were also identified as significant DMRs in the same brain region in a recent meta-analysis, while additional DMRs annotated to 12 genes were reported as DMRs in a different brain region or in a cross-cortex meta-analysis. The significant DMRs were enriched in promoters, CpG islands, and exons in the genome. Gene set enrichment analysis of DMPs and DMRs showed that gene sets involved in neuroinflammation (e.g., microglia differentiation), neurogenesis, and cognition were enriched (false discovery rate (FDR) < 0.05). Conclusions Twenty-two DMPs and 30 DMRs associated with pathology were replicated, and novel DMPs and DMRs were discovered.

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Section: Discussionsupporting

confidence: 70%

Section: Introductionmentioning

confidence: 99%

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confidence: 99%

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Epigenome-wide association study of Alzheimer’s disease replicates 22 differentially methylated positions and 30 differentially methylated regions

Sun

Wang

2020

Clin Epigenet

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“…Furthermore, in the context of AD, LCM would allow the isolation and comparison between NFT-bearing neurons and unburdened neurons within the same sample, which could allow the identification of epigenetic changes prior to the presence of pathology within a cell. LCM has successfully been used in one AD EWAS to date; Hernandez et al [49] isolated pyramidal layer cells in 32 frontal cortex post-mortem brain samples, including 18 AD donors, before profiling on the 450 K array and highlighted differential methylation in several previously nominated loci, including HOXA3 and BIN1, in addition to demonstrating an enrichment of genes associated with oxidative stress and synapsis. However, this study was limited to a small sample number and just explored this single population of cells.…”

Section: Techniques To Address Sample Heterogeneity In Ad Methylomic mentioning

confidence: 99%

Invited Review – A 5‐year update on epigenome‐wide association studies of DNA modifications in Alzheimer’s disease: progress, practicalities and promise

Smith

Wheildon

Lunnon

2020

Neuropathology Appl Neurobio

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In late 2014, the first epigenome‐wide association studies of DNA modifications in Alzheimer’s disease brain samples were published. Over the last 5 years, further studies have been reported in the field and have highlighted consistent and robust alterations in DNA modifications in AD cortex. However, there are some caveats associated with the majority of studies undertaken to date; for example, they are predominantly restricted to profiling a limited number of loci, are principally focused on DNA methylation, are performed on bulk tissue at the end stage of disease and are restricted to nominating associations rather than demonstrating causal relationships. Consequently, the downstream interpretation of these studies is limited. Owing to recent advances in state‐of‐the‐art cell profiling techniques, long‐read genomic technologies and genetic engineering methodologies, identifying cell‐type‐specific causal epigenetic changes is becoming feasible. This review seeks to provide an overview of the last 5 years of epigenomic studies of DNA modifications in Alzheimer’s disease brain samples and propose new avenues for future research.

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“…Levels of 5mC were inversely proportional to the deposition of neurofibrillary tangles in the same hippocampal cells. Hernández et al [33] studied DNA methylation patterns of cortical pyramidal layers in 32 brains of patients with LOAD demonstrating hypermethylation of synaptic genes and genes related to oxidative stress including HOXA3 , GSTP1 , CXXC1-3 and BIN1 .…”

Section: Dna Methylation Studiesmentioning

confidence: 99%

Epigenetic Factors in Late-Onset Alzheimer’s Disease: MTHFR and CTH Gene Polymorphisms, Metabolic Transsulfuration and Methylation Pathways, and B Vitamins

Román

Mancera-Páez

Bernal

2019

IJMS

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DNA methylation and other epigenetic factors are important in the pathogenesis of late-onset Alzheimer’s disease (LOAD). Methylenetetrahydrofolate reductase (MTHFR) gene mutations occur in most elderly patients with memory loss. MTHFR is critical for production of S-adenosyl-l-methionine (SAM), the principal methyl donor. A common mutation (1364T/T) of the cystathionine-γ-lyase (CTH) gene affects the enzyme that converts cystathionine to cysteine in the transsulfuration pathway causing plasma elevation of total homocysteine (tHcy) or hyperhomocysteinemia—a strong and independent risk factor for cognitive loss and AD. Other causes of hyperhomocysteinemia include aging, nutritional factors, and deficiencies of B vitamins. We emphasize the importance of supplementing vitamin B12 (methylcobalamin), vitamin B9 (folic acid), vitamin B6 (pyridoxine), and SAM to patients in early stages of LOAD.

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Alzheimer’s Disease DNA Methylome of Pyramidal Layers in Frontal Cortex: Laser-Assisted Microdissection Study

Cited by 28 publications

References 92 publications

Epigenome-wide association study of Alzheimer’s disease replicates 22 differentially methylated positions and 30 differentially methylated regions

Epigenome-wide association study of Alzheimer’s disease replicates 22 differentially methylated positions and 30 differentially methylated regions

Invited Review – A 5‐year update on epigenome‐wide association studies of DNA modifications in Alzheimer’s disease: progress, practicalities and promise

Epigenetic Factors in Late-Onset Alzheimer’s Disease: MTHFR and CTH Gene Polymorphisms, Metabolic Transsulfuration and Methylation Pathways, and B Vitamins

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