When it comes to understanding the epigenetics of aging, Alzheimer’s Disease (AD) has enhanced our knowledge in countless ways. This neurodegenerative disease has taught us to embrace healthy aging, and some surprising players have emerged from the examination of DNA methylation. Studies have uncovered a role for enhancers in AD; however, investigations into the consequences of DNA methylation at these sequences remain a road not taken. Now, researchers from the lab of Viviane Labrie (Van Andel Research Institute, USA) have paved the way for an enhanced comprehension regarding the role of enhancers in AD.
While the presence of intraneuronal neurofibrillary tangles of the Tau protein and extracellular β-amyloid (Aβ) plaques derived from the amyloid precursor protein (APP) characterize AD, the mechanisms promoting the development of these pathologies remain an area of active investigation. Therefore, the talented team utilized bisulfite padlock probe sequencing, a targeted DNA methylation sequencing method, to explore the role enhancers play during AD development. They designed 59,009 probes to cover the 29,132 currently defined brain enhancers (122,071 CpGs and 1,085,436 CpH sites, where H = A, C, or T) and then examined neuronal nuclei isolated from 101 prefrontal cortex samples from individuals with no/mild, moderate, and severe AD pathology.
Here’s what Li and colleagues discovered:
- 1224 differentially methylated regions are primarily hypomethylated (> 75%)
- The top known transcription factor motif belongs to the ETS family, which controls differentiation, cell cycle, and apoptosis
- The top de novo motif highlights the dominating role of CpH methylation, particularly CpA methylation
- One of the most significant differentially methylated regions (DMRs) maps to a enhancer in DSCAML1 and its hypomethylation precedes the onset of neurofibrillary tangles
- Integration of previously published high-throughput sequencing-based chromosome conformation capture (Hi-C) data revealed that the identified AD enhancers interact in cis with 1942 promoters that belong to 1207 genes
- Pathway analysis highlights the role of these genes in AD-relevant functions related to neurogenesis, neurodevelopment, and brain disorders
- The DSCAML1 enhancer interacts with the nearby BACE1 promoter, which codes for a protein that cleaves APP and plays a critical role in the generation of pathogenic Aβ plaques
- DMR integrative analysis with RNA-sequencing (RNA-seq) data from a subset of the samples uncovered networks related to cell cycle re-entry and amyloid neuropathies
- By analyzing a separate and larger 450K DNA methylation array study with RNA-seq data, the team independently confirmed that the hypomethylation of a single CpG in the DSCAML1 enhancer correlates with altered expression of BACE1 in early-stage AD but not in late stage AD
- Hypomethylation of the DSCAML1 enhancer also correlates with AD pathology and cognitive symptoms
- By examining the relationship between gene expression and genotype (SNPs) in the DSCAML1 region, the team discovered that five haplotypes influence BACE1 expression: three in the gene itself and two in the DSCAML1 enhancer
- Then the group examined the association between age and AD, where they observed a decrease in CpH methylation with age that plateaus in late-stage AD
- They also found that late stage AD patients show accelerated epigenetic aging by employing a customized version of the epigenetic clock
Ultimately, these impressive results led the team to propose an intriguing hypothetical model based on CpH methylation. During early neurodevelopment, CpH methylation accumulates and triggers a transition from proliferation and migration to synapse formation and pruning. However, while CpH methylation decreases later in life, this process is accelerated in AD and reactivates the cell cycle in differentiated post-mitotic neurons and triggers apoptosis rather than encouraging proliferation.
Senior author Viviane Labrie shares, “In adults, brain cells typically are done dividing. When enhancers reactivate cell division, it’s incredibly damaging. The enhancer changes we found also encourage the development of plaques, which act as gasoline for the spread of toxic tangles, propagating them through the brain like wildfire. Taken together, enhancer abnormalities that promote plaques, tangles and cell cycle reactivation appear to be paving the way for brain cell death in Alzheimer’s disease.”
Enhance your perspective of AD in Nature Communications, May 2019