![]() (e) STRING (v11) analysis for the 75 transcription- and chromatin-related genes (in panel d) revealing a protein interaction network of 35 gene products ( top) with CREBBP and EP300 at the center of the network. CREBBP, EP300 and TRRAP are highlighted in red. (D) Heatmap showing gene expression in Younger, Old and AD for genes that are in the GO term “Regulation of transcription” in panel b (N = 75). (b,c) Barplot showing top GO terms (Biological Process, DAVID, FDR < 10%, Yekutieli) for genes that are significantly (b) upregulated or (c) downregulated in AD vs. Red dots represent significant differentially expressed genes (q < 0.05, DESeq2). (a) Scatterplot showing gene expression changes vs. Linear regression trendlines, Pearson’s correlation coefficients and p-values (test for association using Pearson’s product moment correlation coefficient implemented by R stats package, two-sided) are indicated in each panel (a-l). The closest peak to the TSS was chosen for these analyses. (l) Scatterplot of H3K-total-ac absolute peak fold-change vs absolute gene expression change for significantly ( q < 0.05) differentially expressed genes in AD vs Old. (j,k) Scatterplot of total acetyl-peak enrichment (H3K-total-ac sum of H3K27ac, H3K9ac and H3K122ac peak enrichment at the same site) vs gene expression for genes expressed in (j) Old and (k) AD. (g-i) Scatterplot of (g) H3K27ac, (h) H3K9ac and (i) H3K122ac absolute peak fold-change vs absolute gene expression change for significantly ( q < 0.05) differentially expressed genes in AD vs Old. For graphical representation in a-b, 3000 randomly chosen points are shown in each panel. (d-f) Scatterplot of (d) H3K27ac, (e) H3K9ac and (f) H3K122ac peak enrichment vs gene expression for genes expressed in AD. (a-c) Scatterplot of (a) H3K27ac, (b) H3K9ac and (c) H3K122ac peak enrichment vs gene expression for genes expressed in Old. The identification of this process highlights potential epigenetic strategies for early-stage disease treatment. Together, these findings suggest that AD involves a reconfiguration of the epigenome, wherein H3K27ac and H3K9ac affect disease pathways by dysregulating transcription- and chromatin-gene feedback loops. Increasing genome-wide H3K27ac and H3K9ac in a fly model of AD exacerbated amyloid-β42-driven neurodegeneration. In turn, epigenomic profiling revealed gains in the histone H3 modifications H3K27ac and H3K9ac linked to transcription, chromatin and disease pathways in AD. An unbiased proteomic screening singled out H3K27ac and H3K9ac as the main enrichments specific to AD. RNA sequencing analysis revealed upregulation of transcription- and chromatin-related genes, including the histone acetyltransferases for H3K27ac and H3K9ac. Here we integrated transcriptomic, proteomic and epigenomic analyses of postmortem human brains to identify molecular pathways involved in AD. aggregation is the hallmark of neurodegeneration, but the molecular mechanisms underlying late-onset Alzheimer's disease (AD) are unclear. 12 Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 11 Department of Biology, University of Pennsylvania, Philadelphia, PA, USA. 10 Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 9 Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 8 Department of Biology, University of Pennsylvania, Philadelphia, PA, USA.7 Department of Chemistry, Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics, Howard Hughes Medical Institute, University of Chicago, Chicago, IL, USA.6 Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.5 Department of Biology, University of Pennsylvania, Philadelphia, PA, USA.4 Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, USA.3 Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.2 Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.1 Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |