Genome-wide alteration of 5-hydroxymethylcytosine in a mouse model of Alzheimer's disease Open Access

Shu, Liqi (2015)

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Alzheimer'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. Strong evidences have indicated the implication of epigenetic modifications, including histone modification and DNA methylation, in AD. Recent studies revealed that 5-hydroxymethylcytosine (5hmC)-mediated DNA demethylation is dynamically regulated during neurodevelopment and aging. Here we show that amyloid peptide 1-42 (Aβ-42) could significantly reduce the global level of 5hmC in cell cultures. We found that the global 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. Our genome-wide profiling study identified differential hydroxymethylation regions (DhMRs) in DTg mice, which were highly enriched almost everywhere, for example, introns, exons and intergenic regions. Gene ontology analysis indicated that DhMR-associated genes are highly enriched in multiple signaling pathways involving neuronal development/differentiation and neuronal function/survival. Our results strongly argue that 5hmC-mediated epigenetic regulation could contribute to the pathogenesis of AD.

Table of Contents

Introduction. 1 to 6

Methods. 7 to 10

Results. 11 to 14

Discussion. 15 to 19

Figures. 20 to 23

References. 24 to 28

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