GSE126713
Loss of TET3-mediated 5hmC promotes the Neurodegeneration of Alzheimer's disease
Alzheimer's disease (AD) was attributed to alterations in multiple epigenetic systems including DNA methylation and demethylation patterns. DNA 5-hydroxymethylcytosin (5hmC), an epigenetic hallmark, plays importantly regulatory role in many biological processes. However, the 5hmC-mediated epigenetic underpinnings of AD neurodegeneration remain poorly understood. Here we report that selective loss of 5hmC is substantially presented in human AD and 3xTg-AD mouse neocortical and hippocampal neurons. Quantitative genome-wide analysis of hMeDIP-seq reveals that neuron-specific shift in decreased 5hmC enrichment in regions of promoter, intergenic and gene body of mRNA and lncRNA genes was found in3xTg-AD mice. We further identified that TET3, an enzyme that converts 5-methylcytosine (5mC) to 5hmC, responded to Beta amyloid neuronal toxicity and was mainly responsible for loss of 5hmC in AD brain. Overexpression of human TET3 catalytic domain (hTET3CD) significantly improves the neuroinflammation, neuropathological progression and cognitive deficits in 3xTg-AD mice. These findings implicate as a potential hallmark, TET3-mediated 5hmC epigenetic dysregulation is involved in driving AD neurodegeneration. Overall design: There are four groups, wild type and 3xTg-AD mouse cortical neurons; wild type and 3xTg-AD mouse cortical astrocytes. For each group, genomic DNA samples were immunoprecipitated with anti-5hmC (n=3). There were also three replicates of input control for each group.