Reading Between the Lines: The Epigenome in Alzheimer’s Disease

There’s more information in the genome encoded than just the base-code sequence in DNA. The epigenome, defined as data accessible above the genome, is characterized by protein binding and chemical modifications. The epigenome has been implicated as the mechanism by which environment plays a role on our development and now, researchers have finally turned an eye to the role of the epigenome in Alzheimer’s disease.

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Figure 1: The epigenome has accessible information that we could use to target diseases like Alzheimer’s [Photo Link]
In 2014, the field of epigenetics was in its infancy. This was evident when two papers, Jager et al. [1] and Lunnon et al. [2], were sufficient to comprise a Nature review titled: The Epigenetic Landscape of Alzheimer’s Disease.

So you may be asking yourself, “What did Jager et al. and Lunnon et al. do that validates this overarching generalization? In essence, both groups performed an assay for CpG dinucleotide islands, the most common epigenetic chemical modification of DNA (methylation), to assess the methylation status of the entire epigenome. Afterwards, they both performed statistical analysis to verify that their methylated dinucleotide islands did in fact correlate to Alzheimer pathology. What set the precedent for their success was their independent validation of each other’s results and the novelty of their discovery.

Part of the problem with brain diseases is that we’re still shooting in the dark in terms of molecular biomarkers for determination of progression of disease. In order to combat disease, we must first study our opponent. Fortunately, tools like epigenomics can help us locate points of weakness more precisely. In fact, in this study, Jager et al. and Lunnon et al. both independently found multiple gene loci significantly correlated to Alzheimer’s that had not been identified previously: ANK1RPL13RHBDF2 as a few examplesJust like how it’s efficient to do problems independently when working problems with a friend, then going back to cross-check answers, Jager et al. and Lunnon et al. arrived at this conclusion separately, which is surprisingly rare in the scientific field.

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Figure 2: Genes in bold and red correlated with Alzheimer’s [Photo Link]
As I’ve stated in my previous article, well-known symptoms of Alzheimer’s disease namely include neurofibrillary tangles and beta-amyloid plaques. However, there is much more complexity and interplay in the details. For example, when Lunnon et al. was trying to look at brain slices, she noticed that parts of the brain were differentially susceptible to neurofibrillary tangles. In fact, portions of the brain, i.e. the entorhinal cortex quickly falls prey to neurofibrillary tangles early in Alzheimer’s, while other regions of the brain like the cerebellum stay fairly resistant to the damage.

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Figure 3: A combination of normal bisulfite sequencing and a microarray allows the Illumina chip to assay 450,000 sites for methylation [Photo Link]
Interestingly, both Lunnon et al. and Jager et al. assayed their epigenomic results in two ways: they utilized Illumina’s 450K array and bisulfite sequencing to confirm their results. [3] Bisulfite sequencing converts non-methylated cytosine bases into uracils which can be detected for by sequencing. Consequently, methylated cytosine bases would still appear as normal cytosines.

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Figure 4: A protocol for bisulfite sequencing that both papers used. [Photo Link]
What Jager et al. found was that a region near ANK1, a previously uncharacterized gene,  had clearly differential methylation that was correlated to Alzheimer’s. Using epigenomics, Jager et al. had found another possible target for treatment. Impressively, Jager et al. validated their results very logically, by looking at mRNA transcripts to follow up on the regulation of their genes after determining that its methylation status was correlated to Alzheimer’s. Moreover, Jager et al. projected forward, predicting that precise mapping of different regions of the cortex would soon follow in the future.

However, in my opinion, Lunnon et al. did a wonderful job in the conclusion of summarizing the results. In general, the four paragraph discussion quickly went over the main confounders of working with epigenetic studies and problems for determining significance statistically. The wrap-up of the article piece with blood from patients’ brain being an area of future exploration was also a neat way to end the article. Also, because I’ve only rarely got to see similar information presented in different ways, I’ve really appreciated that she condensed her findings into a manageable block of information.

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Figure 5: The field of epigenetics has progressed much further since these two papers, but their role in instigating future studies is historical. [Photo Link]
In conclusion, both Lunnon et al. and Jager et al. provided a basis for researchers to expand their understanding of epigenetics in neurodegenerative diseases. Although there were only two papers that comprised the majority of the field in 2014, the importance of having replicable results cannot be understated. The robust nature of the two independent studies sparked the field as a whole and lent credence to the idea that there is more genetic information in our body than just the simple base pair sequences.

Our DNA is telling us to read between the lines.

References:

  1. De Jager, Philip L., et al. “Alzheimer’s disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci.” Nature neuroscience 17.9 (2014): 1156-1163.
  2. Lunnon, Katie, et al. “Methylomic profiling implicates cortical deregulation of ANK1 in Alzheimer’s disease.” Nature neuroscience 17.9 (2014): 1164-1170.

 

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