Untangling the Role of Tau on the Epigenome of Alzheimer’s Brains
Forgetting where you put your car keys or the address of your aunt’s house is pretty normal, but for people with Alzheimer’s disease, this kind of forgetfulness and memory loss is just the tip of the iceberg. As the neurons in the brains of these patients degenerate, their memory loss gets progressively worse over time . Some genetic mutations have been identified that cause Alzheimer’s in middle-aged people, but for the majority of patients with Alzheimer’s who do not develop the disease until around 80 years old, the factors that lead to it remain unknown .
Scientists and clinicians do have some leads, however, in the form of two proteins called tau and amyloid-β which form tangles and plaques, respectively, in the brains of patients with Alzheimer’s . In an effort to better understand the changes that occur in the brain as a result of Alzheimer’s disease, Klein et al, in a new study published in Nature Neuroscience, assessed the epigenome of 669 people with aged brains. Previous studies with smaller numbers of human subjects have suggested that epigenetic changes occur in brains of Alzheimer’s patients , so Klein and colleagues aimed to understand this connection more deeply by studying the epigenomes of a larger number of people with aging and Alzheimer’s disease affected brains.
Using chromatin-immunoprecipitation sequencing (ChIP-seq) for acetylation of the ninth lysine on histone 3 (H3K9ac), the researchers isolated the regions of aged or Alzheimer’s brains that contained this active chromatin mark, indicating that these regions of the DNA were open and likely being expressed. Interestingly, when the researchers modeled how many of the H3K9ac sites were associated with different factors like age, gender, amyloid-β, or tau, they found that 23% of the H3K9ac sites were associated with tau, as opposed to just 2% of the sites being associated with amyloid-β.
When Klein et al looked closer to identify where these tau-associated H3K9ac domains were located in the genome, they were surprised to find that these tau-associated regions covered several megabase pairs in length. A megabase measures 1,000,000 base pairs, which covers a substantial part of the human chromosome. Because these tau-associated regions are so large, it would suggest that tau may be influencing the chromosome as a whole: perhaps by altering its overall structure or structural arrangement in the nucleus. Supporting this, the researchers found that when they considered the chromatin on the megabase pair scale, type-A compartments (open chromatin) were affected by tau significantly more than type-B compartments (closed chromatin). This result suggests that the spatial arrangement of the chromosome is associated with the effect of tau on H3K9ac sites.
To test this idea further, the researchers asked how much the H3K9ac tau-associated regions associated with the nuclear lamina. The nuclear lamina is a structure on the inner surface of the nucleus and is involved in processes like cell division, chromatin organization, and DNA replication . It is associated with heterochromatin, but recent studies have shown that tau can disrupt the lamina and cause the heterochromatin to become more open . In their study, Klein et al found that how much tau affected a single H3K9ac domain depended on how much the regions surrounding that H3K9ac site associated with the nuclear lamina, thus the association of tau with certain H3K9ac domains is related to chromatin organization.
Klein et al next asked that if they over-expressed the gene that encodes tau in neurons, would they see these same epigenetic changes? Using the Assay for Transposase-Accessible Chromatin with sequencing (ATAC-seq), they found large megabase regions that were associated with tau, a significant difference between the effect of tau on type-A versus type-B compartments, and an association with the nuclear lamina. These results demonstrated that over-expression of tau leads to the same large-scale epigenome changes seen in aging brains.
To counteract the alterations tau makes to chromatin structure, the researchers looked for a compound that had a gene expression profile that was opposite that of the H3K9ac tau-associated regions. They identified the compound 17-DMAG (alvespimycin) and found that by treating neurons over-expressing tau with 17-DMAG, they could protect these cells from the detrimental effect of tau.
Overall, this study shows that tau influences structural changes to chromatin in aging and Alzheimer’s brains, and that there are large-scale changes to the epigenome in these brains. This study also identifies a possible treatment, 17-DMAG, for these chromatin alterations and serves as the basis for future studies into the mechanisms underlying Alzheimer’s disease.
Original article: Klein HU, McCabe C, Gjoneska E, Sullivan SE, Kaskow BJ, Tang A, Smith RV, Xu J, Pfenning AR, Bernstein BE, Meissner A, Schneider JA, Mostafavi S, Tsai LH, Young-Pearse TL, Bennett DA, De Jager PL (2019). Epigenome-wide study uncovers large-scale changes in histone acetylation driven by tau pathology in aging and Alzheimer’s human brains. Nat Neurosci, 22(1): 37-46. doi: 10.1038/s41593-018-0291-1.
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