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Assignment 2

Main Objective and Conclusions:
The researchers' main objectives with this study were to better understand chromatin state alterations during neurodegeneration caused by Alzheimer's disease, and to establish mice as useful model organisms for studies involving Alzheimer's disease. They concluded that the depletion of neuronal promoters and enhancers are important loci associated with Alzheimer's disease, along with previously determined loci associated with immune genes, in light of the environmental and experiential factors that contribute to the disease. Further, they found that model organisms, specifically mice, are extremely valuable in studies of human disease progression. Finally, using the model organisms, researchers were able to pinpoint specific targets for therapy in treating Alzheimer's disease. While I think this is a good paper in general, because it does a good job of leading the reader from one conclusion to the next and ties the first two figures into the third in a satisfying way, there were a couple of panels that were unclear. I also would have like to see more explicit denotation of significance or otherwise within a couple of the figures.
GeneEnrichment

Figure 1: This figure shows gene expression changes in both mice humans with Alzheimer's disease. Panel a depicts changes in gene expression for six different temporal classes in eleven of the most significant Gene Ontology categories. Panel b corresponds to Panel a in that it shows the T-statistic of gene expression change for each temporal class, but this time in humans with Alzhemier's disease instead of in mice. Panel c is supposed to depict human gene expression change per temporal class in patients with Alzheimer's disease compared to a control, but it is unclear where the control data versus patient data are in the panel. Panels d and e show promoter states and enhancer states in mice, and the enrichment of each Gene Ontology category was calculated with respect to those states. Panels f and g show the enrichment of the regulatory motifs in promoters and enhancers, which are the top and bottom of each panel respectively; Panel f is a control, and Panel g is conducted with mice modeling human Alzheimer's disease. Panels h and i show where promoters and enhancers within the mouse models overlap with neuronal and immune transcriptional factors, showing that gene expression changes in humans with Alzhemier's disease and the mouse models are related to immune and neuronal funcions.

Overlap 

Figure 2: Panel a shows the fold enrichment in different cell types in the mouse models of human Alzheimer's disease for each of the six temporal classes that were shown in figure one. Highlighted are the cell types that were determined in the previous figure as having a bearing on gene expression change in Alzheimer's disease patients. In Panel b, enrichment in microglia (orange) and neural (purple) cells in the mouse model for Alzheimer's disease was compared to a control, and across the board microglia cells had higher enrichment, measured in fold difference in luminescence, than the microglia control cells did. Neuronal cells had much higher enrichment in neuronal cells compared to the control for the enhancer region BIN1. Panel c shows that the consistent increase temporal class showed enhanced enrichment in SNPs associated with Alzheimer's disease in humans. Panels d and e plot human enrichment in SNPs associated with Alzheimer's disease against enrichment in changing enhancers in the Alzheimer's disease mouse model. In the increasing consistent temporal class, there appears to be some sort of linear trend between the two (R^2=0.49), but in the decreasing consistent temporal class, there appears to be no linear trend between the two (R^2=0.05).

ImmuneLoci 

Figure 3: This figure attempts to find non-coding loci associated with Alzheimer's disease in humans, by finding the location of human orthologues for the increasing enhancers found in the mouse models. Panels a, b, and c show the overlap of SNPs associated with Alzheimer's disease in humans with enhancers in the mouse model and with three human genome-wide immune enhancers in humans (SNPs are the top section of each panel, enhancer in mouse are the next row down, and human immune enhancers is the row below that). The overlaps in each panel, denoted by the pink columns, represent non-coding loci that may be associated with Alzheimer's disease in humans. Panel d takes three variants of the SNP in Panel b and quantifies the enrichment for each, showing that the third variant (SPI1 rs1377416) has significantly higher enrichment than the other two variants. I am a little confused as to why significance from the control was not denoted in this panel.

I think this is a good paper in general, because it does a good job of leading the reader from one conclusion to the next and ties the first two figures into the third in a satisfying way.  A couple of the panels were unclear in that I would have liked to see more explicit denotation of significance or otherwise within them. Overall though, I thought this paper led the reader through the research and data in a way that made the conclusions clear.

Literature Cited:
Gjoneska, Elizabeta et al. "Conserved Epigenomic Signals in Mice and Humans Reveal Immune Basis of Alzheimer's Disease." Nature 518 (2015): 365-369.


Email Questions or Comments: emparker@davidson.edu