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P1–054: An exploration of a functional unit of DNA methylation in the aging brain
Author(s) -
Keenan Brendan,
Srivastava Gyan,
Chibnik Lori,
De Jager Philip,
Bennett David,
Schneider Julie
Publication year - 2013
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2013.05.275
Subject(s) - cpg site , dna methylation , methylation , epigenetics , biology , differentially methylated regions , human genome , genome , genetics , correlation , computational biology , evolutionary biology , dna , gene , gene expression , geometry , mathematics
post-mortem brain tissue. Methods: Neuropathological specimens were dissected from 24 age, sex and race-matched temporal pole (BA 38) samples: 8 each from LOAD, DLB, and CN tissues. DNA Methylation patterns from each sample were quantitated using the Illumina Infinium HumanMethylation450 bead chip array. To examine the effects of methylation on transcription, RNA-seq was done on all samples. Total RNAwas prepared using Epicentre’s script-seq library protocol and sequenced on Illumina’s HiSeq2000. Reads were aligned using GSNAP and assembled into transcripts using Cufflinks. Both data sets were analyzed using R statistical software.Results:Methylation of CpG sites in LOAD compared to CN revealed no global differences between the two groups. A comparison of LOAD to DLB demonstrated hypermethylation of DLB relative to both LOAD (p1⁄40.0006) and CN (p1⁄40.02). Methylation differences between LOAD and DLB were mainly located in CpG islands (p1⁄40.001) and within CpG shores (p1⁄40.002). CpG islands with the greatest differential methylation between the groups were located near genes involved in cell junctions and synaptic functions (p<0.016). RNA-Seq data was analyzed to see if 2,100 transcripts with differential methylation were differentially expressed. We found 95 transcripts to have differential expression between LOAD and DLB. 168 transcripts were differentially expressed between LOAD and CN and 175 transcripts were differentially expressed between DLB and CN.Conclusions: DNAmethylation analysis reveals no global changes between LOAD and CN. A significant number of CpG sites in DLB were hypermethylated compared to LOAD and CN. This hypermethylation in DLB did not correlate with changes in gene expression when compared to LOAD, but did correlate with expression differences between DLB and CN. Investigation of methylation’s effects on gene splicing and isoform expression is underway. These findings show DNA methylation is substantially different between LOAD and DLB with potential major implications for the understanding of the etiology of both disorders.