5-Hydroxymethylation-associated epigenetic modifiers of Alzheimer’s disease modulate Tau-induced neurotoxicity

Abstract

Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by progressive deterioration of cognitive function. Pathogenesis of AD is incompletely understood; evidence suggests a role for epigenetic regulation, in particular the cytosine modifications 5-methylcytosine and 5-hydroxymethylcytosine (5hmC). 5hmC is enriched in the nervous system and displays neurodevelopment and age-related changes. To determine the role of 5hmC in AD, we performed genome-wide analyses of 5hmC in DNA from prefrontal cortex of post-mortem AD patients, and RNA-Seq to correlate changes in 5hmC with transcriptional changes. We identified 325 genes containing differentially hydroxymethylated loci (DhMLs) in both discovery and replication datasets. These are enriched for pathways involved in neuron projection development and neurogenesis. Of these, 140 showed changes in gene expression. Proteins encoded by these genes form direct protein-protein interactions with AD-associated genes, expanding the network of genes implicated in AD. We identified AD-associated single nucleotide polymorphisms (SNPs) located within or near DhMLs, suggesting these SNPs may identify regions of epigenetic gene regulation that play a role in AD pathogenesis. Finally, using an existing AD fly model, we showed some of these genes modulate AD-associated toxicity. Our data implicate neuronal projection development and neurogenesis pathways as potential targets in AD. By incorporating epigenomic and transcriptomic data with genome-wide association studies data, with verification in the Drosophila model, we can expand the known network of genes involved in disease pathogenesis and identify epigenetic modifiers of Alzheimer's disease.

Single-Base Resolution Mapping of 5-Hydroxymethylcytosine Modifications in Hippocampus of Alzheimer’s Disease Subjects

“…Advances in loci- specific techniques to study whole epigenomes have increased greatly in the past several years, however the cost of this new technology is high, limiting the number of subjects per analysis. Although samples sizes were small, two previously published studies of differentially hydroxymethylated regions of the AD genome in prefrontal cortex tissue specimens (Bernstein et al 2016, Zhao et al 2017) showed several overlapping genes with altered hydroxymethylation in our gene list. One gene common to all three genome-wide 5-hmC studies in AD brain, myelin transcription factor 1-like ( MYT1L ), was used to produce induced neuronal cells and has been described as a neuronal fate inducing factor (Vierbuchen et al .…”

Epigenetic modulation of AREL1 and increased HLA expression in brains of multiple system atrophy patients

“…Specifically, 5-methylcytosine (5mC) is recognized as an important regulator of gene expression [14], but is not the only DNA-based epigenetic modification. 5-Hydroxymethylcytosine (5hmC), another equally important epigenetic regulator, is widely distributed in the brain [15] and is implicated in fetal brain development [16] as well as in different brain disorders [17,18]. Disease-specific differences in global 5mC and 5hmC levels have been reported in selected areas of the brain in MSA patients by immunodetection [19].…”

Characterization of DNA hydroxymethylation in hypothalamus of elderly mice with postoperative cognitive dysfunction

“…The recent studies has revealed that the level of 5hmC reduced 10% after ten-eleven-translocation 1 (Tet1) knockdown can retard the proliferation of neural progenitor cells and impair the abilities of spatial learning and memory (Rudenko et al, 2013; Zhang et al, 2013). Moreover, declining 5hmC modulates transcriptional activity of some genes involved in neurogenesis in AD mice, which also indicates that 5hmC closely connects with memory maintenance (Bernstein et al, 2016; Shu et al, 2016). Besides Tet family, Ubiquitin-like with PHD and ring finger domains 2 (Uhrf2) is currently considered as a novel regulator via its SRA domain (Zhou et al, 2014) to maintain 5hmC level and abilities of learning and memory in brain (Chen et al, 2017b).…”