Genome-wide alteration of 5-hydroxymenthylcytosine in a mouse model of Alzheimer’s disease

Abstract

BackgroundAlzheimer’s disease (AD) is the most common form of neurodegenerative disorder that leads to a decline in cognitive function. In AD, aggregates of amyloid β peptide precede the accumulation of neurofibrillary tangles, both of which are hallmarks of the disease. The great majority (>90 %) of the AD cases are not originated from genetic defects, therefore supporting the central roles of epigenetic modifications that are acquired progressively during the life span. Strong evidences have indicated the implication of epigenetic modifications, including histone modification and DNA methylation, in AD. Recent studies revealed that 5-hydroxymethylcytosine (5hmC) is dynamically regulated during neurodevelopment and aging.ResultsWe show that amyloid peptide 1–42 (Aβ1-42) could significantly reduce the overall level of 5hmC in vitro. We found that the level of 5hmC displayed differential response to the pathogenesis in different brain regions, including the cortex, cerebellum, and hippocampus of APP-PSEN1 double transgenic (DTg) mice. We observed a significant decrease of overall 5hmC in hippocampus, but not in cortex and cerebellum, as the DTg mice aged. Genome-wide profiling identified differential hydroxymethylation regions (DhMRs) in DTg mice, which are highly enriched in introns, exons and intergenic regions. Gene ontology analyses indicated that DhMR-associated genes are highly enriched in multiple signaling pathways involving neuronal development/differentiation and neuronal function/survival.Conclusions5hmC-mediated epigenetic regulation could potentially be involved in the pathogenesis of AD.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-2731-1) contains supplementary material, which is available to authorized users.

Quantification of DNA methylation and hydroxymethylation in Alzheimer's disease mouse model using LC‐MS/MS

“…5hmC, the sixth base of genome, was revealed that it not only served as an intermediate embodied in DNA methylation pathway, but can also perform as a stable epigenetic marker to indicate the disease development . In this study, significant increase of 5hmC in 3 month‐age of AD mouse was found when compared with age‐matched WT control, demonstrating elevated 5hmC accumulation was positively correlated with the occurrence of AD and steadily presented in various stages of this disorder.…”

DNA Methylation in Neurodegenerative and Cerebrovascular Disorders

“…Different authors have described a decrease of 5mC or 5hmC levels in brains and blood samples in different animal models and human samples of these disorders [28][29][30][31][32][33][34][35]. Indeed, Aβ1-42 peptide reduces 5hmC levels in vitro [36]. Different brain regions have different 5hmC levels, with reduced 5hmC levels in the hippocampus but not in the cortex or cerebellum [36].…”

“…Indeed, Aβ1-42 peptide reduces 5hmC levels in vitro [36]. Different brain regions have different 5hmC levels, with reduced 5hmC levels in the hippocampus but not in the cortex or cerebellum [36]. High hydroxymethylation regions are enriched in introns, exons and intergenic regions, and genes associated with these hydroxymethylated regions are implicated in neuronal development/differentiation and neuronal function/survival pathways [36,37].…”

Chemo brain or tumor brain - that is the question: the presence of extracranial tumors profoundly affects molecular processes in the prefrontal cortex of TumorGraft mice

“…In conjunction with DNA methylation, hydroxyl-methylation regulates tissue-specific gene expression patterns [ 71 ]. Altered hydroxymethylation levels have been reported to occur in autism [ 72 ], Alzheimer's disease [ 72 ], intracerebral hemorrhage [ 73 ], and other conditions. Hydroxymethylation levels were affected by proton exposure [ 68 ] and chemotherapy [ 21 ].…”