Cell type-specific histone acetylation landscape in Alzheimer's disease reveals a putative role of MITF in microglia

Alzheimer's disease (AD) is characterized by abnormal amyloid beta and tau clumping, immune system inflammation, nerve damage and cell death. These symptoms are thought to arise from alterations in cell-specific gene activity. Histone acetylation, a process that influences gene expression, is a key player in these transcriptional changes.

While global modifications in histone acetylation have been observed in AD, the role of specific cell types in these epigenetic shifts is not well understood. To examine cell-type-specific changes in gene regulation in AD, researchers analyzed histone H3 lysine 27 acetylation (H3K27ac) in microglia, oligodendrocytes, and neurons from the prefrontal cortex of individuals with late-stage AD and non-dementia controls.

Oligodendrocytes displayed the greatest number of differentially acetylated regions in AD, followed by microglia. Genes nearest to these differentially acetylated regions in purified microglia were enriched for genes involved in phagocytosis, lipid processing, inflammation, and disease-associated cellular states. Genomic analysis revealed downregulation of genes maintaining cellular homeostasis in AD microglia and upregulation of immune activation genes, including those linked to lipid-handling and monocyte-derived macrophages.

Oligodendrocyte co-regulated regions indicated increased expression of major histocompatibility complex class I antigens and altered interactions between neurons and oligodendrocytes in AD. The researchers identified histone acetylation allele-specific variants (ASVs) enriched near genes associated with endolysosomal and ubiquitin-proteasome pathways in microglia and neurons.

These ASVs aligned with known Alzheimer's disease genetic risk loci, such as CLU in oligodendrocytes and HLA-DRB1 in microglia. By studying DNA binding motifs, the researchers found that transcription factor MITF, along with the Cap n collar family (BACH1 and NFE2) and AP-1 activation, were implicated in microglial dysregulation in AD.

Furthermore, MITF protein binding in human microglia was localized to lysosomal-associated genes and enriched in H3K27ac regions upregulated in AD and in genes associated with disease-associated microglia. These findings suggest that lysosomal dysfunction and the upstream regulation of genes by MITF play crucial roles in AD microglia.