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Epigenomic Aberrations in Brains of Humans with Mild Cognitive Impairment and Alzheimer’s Disease [re-analysis]

ABSTRACT: Epigenetic mechanisms, particularly histone modifications at gene promoters, are crucial for controlling gene transcription. During the progression of neurodegenerative disorders, epigenomic aberrations may contribute to gene dysregulation, leading to manifestation of symptoms. To test this, we employed a multifaceted approach to investigate how the two key histone methylation marks, H3K4me3 (linked to gene activation) and H3K27me3 (linked to gene suppression), are altered in postmortem prefrontal cortex of humans with Mild Cognitive Impairment (MCI) or Alzheimer’s Disease (AD). Compared to controls, MCI and AD exhibited pronounced losses of permissive H3K4me3 peaks at promoters of genes enriched in synaptic plasticity and neurotransmission, and significant gains of H3K4me3 peaks at promoters of genes enriched in transcriptional regulation. AD displayed more substantial H3K4me3 losses on synaptic genes than MCI. Conversely, significant gains of repressive H3K27me3 peaks were observed at synaptic gene promoters in both disease groups, with MCI exhibiting more pronounced H3K27me3 gains on synaptic genes than AD. Weighted Gene Correlation Network Analysis (WGCNA) revealed multiple modules characterizing distinct patterns of gains and losses of H3K4me3 and H3K27me3 during the transition from MCI to AD. Integrative analysis of epigenomic and transcriptomic data indicated that these histone mark alterations were well correlated with the downregulation of synaptic genes and upregulation of transcriptional regulators in AD. This comprehensive profiling uncovers a stage-dependent reorganization of histone modifications at critical gene loci, implicating these events in the molecular cascade of AD pathogenesis. Targeting dysregulated chromatin states may offer novel therapeutic avenues for early intervention of AD.

PROVIDER: GSE304086 | GEO | 2026/03/17

REPOSITORIES: GEO

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Project description:Epigenetic priming factors establish a permissive epigenetic landscape which is not required until a later developmental or physiological time point, temporally uncoupling the presence of these factors with their phenotypic effects. One classic example of epigenetic priming is in the context of bivalent chromatin, found in pluripotent stem cells and early embryos at key developmental gene promoters marked by both activating-associated H3K4me3 and repressive-associated H3K27me3 histone modifications. It is currently unknown how these bivalent domains are targeted, or precisely how they impact on lineage commitment. Here we show that the small heterodimerising non-enzymatic DNA binding proteins Developmental Pluripotency Associated 2 (Dppa2) and 4 (Dppa4) act as epigenetic priming factors to establish bivalency at a subset of developmental genes. Dppa2/4 localise to the +1 nucleosome position of bivalent genes and while they are not required for pluripotency in embryonic stem cells (ESCs), double knockout cells fail to exit pluripotency and to differentiate efficiently, with delays in upregulating bivalently marked lineage genes. Proteomics reveal that Dppa2/4 interact on chromatin with members of the COMPASS and Polycomb complexes important for H3K4me3 and H3K27me3 deposition, respectively. Epigenetic profiling reveals a striking loss of H3K4me3, H3K27me3, and their associated enzymatic machinery at a significant subset of bivalent promoters in Dppa2/4 mutants, in addition to loss of H2A.Z and chromatin accessibility. In wild-type ESCs, these “Dppa2/4-dependent” bivalent promoters are characterised by low H3K4me3 enrichment and breadth, near-absent expression levels and initiating but not elongating RNA polymerase. Notably, Dppa2/4-dependent promoters are less evolutionarily conserved suggesting that they lack additional safeguard measures to maintain bivalency at these genes in the absence of Dppa2/4. Concomitantly with the loss of bivalency, Dppa2/4-dependent bivalent promoters gain DNA methylation and consequently are no longer able to be effectively activated upon ESC differentiation, leading to defects in cell fate acquisition. Our findings reveal a targeting principle for bivalency to developmental gene promoters poising them for future lineage specific gene activation.

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Epigenomic Aberrations in Brains of Humans with Mild Cognitive Impairment and Alzheimer’s Disease [re-analysis]

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