Widespread H3K27ac differences associated with Alzheimer’s disease in the entorhinal cortex

Building on our previous work exploring DNA methylation in Alzheimer’s disease (AD), a new paper from our group just published in Nature Neuroscience has identified extensive differences in the histone modification H3K27ac associated with AD neuropathology. We quantified genome-wide patterns of H3K27ac in entorhinal cortex samples from AD cases and matched controls using chromatin immunoprecipitation and highly parallel sequencing (ChIP-seq). We observed widespread acetylomic variation associated with AD neuropathology, identifying 4,162 differential peaks (FDR < 0.05) between AD cases and controls. Differentially acetylated peaks were enriched in disease-related biological pathways and included regions annotated to genes involved in the progression of Aβ and tau pathology (e.g. APP, PSEN1, PSEN2, and MAPT), as well as regions containing variants associated with sporadic late-onset AD. Partitioned heritability analysis highlighted a highly-significant enrichment of AD risk variants in entorhinal cortex H3K27ac peak regions. AD-associated variable H3K27ac was associated with transcriptional variation at proximal genes including CR1, GPR22, KMO, PIM3, PSEN1 and RGCC. In addition to identifying molecular pathways associated with AD neuropathology, we present a framework for genome-wide studies of histone modifications in complex disease. Our results can be explored as UCSC Genome Browser tracks and the raw H3K27ac ChIP-seq data is available to download from GEO.