Figure 6. Cell identity loss and epigenome erosion in late-stage AD.
A. UMAP for snATAC-seq (TSS-enrichment>1), colored by major cell types.
B. Major and de-identified cell type compositional changes in snATAC-seq comparing late-stage AD to control and early-stage AD (Anova using propeller, inset for magnification).
C. Scatterplot of the fraction of de-identified oligodendrocytes in this study versus the fraction of undetermined/dying snRNA cells from Kousi et al.46 for the 9 individuals shared between the two studies. Boxplots show cell-fraction comparisons between AD groups within each study (Wilcoxon).
D. Log fold change of the fraction of reads in chromatin states (ChromHMM) between de-identified cells vs. the corresponding normal cells for four major cell types.
E. Example pseudo-bulk ATAC signal for normal and de-identified cells in cell-type-specific peaks (blue box) and constitutive peaks (yellow). Right panels show the signal distribution in intergenic regions.
F. UMAP of cell-level erosion scores, quantified based on the distribution of reads in ChromHMM states (higher score represents increased erosion).
G. Erosion score comparison between different AD groups in each cell type (Wilcoxon).
H. Average oligodendrocyte ATAC profiles at compartment A/B boundaries (left/right) for non-AD, early-AD and late-AD participants. Barplots show difference of means within compartments after/before A/B boundaries (insets) and the difference between the aggregate signals (bottom panels).
I. Difference between boundary A and B for each AD group in each cell type.
J. Joint immunostaining of Lamin-B1 and NeuN on a low-erosion MFC sample. The inset shows a single z-stack with LaminB1/NeuN/Hoechst together (top left), NeuN (bottom left), Lamin B1 (top right) and Hoechst (bottom right) in the bottom panel.
K. Examples of low and high erosion samples at two magnifications (left and center, Lamin B1 and Hoechst). Intensity of Lamin B1 expression was measured on masks created around NeuN-positive cell surfaces. Quantification of LaminB1 intensity (right) across 5 low (n= 91 to 164 NeuN-positive cell surfaces) and 5 high erosion samples (n= 85 to 173) (t-test).
L. Differential TF motif enrichments between de-identified cells versus normal cells for excitatory neurons (green), inhibitory neurons (light green) and oligodendrocytes (orange) based on chromVar (from TF regulators in Figure 1G).