Epigenetic Modulation Through KAT5/HDAC2 Regulates Synaptic Genes in a Disease‐State Specific Manner

Abstract

AbstractBackgroundThe balance between histone acetylation and deacetylation by lysine acetyltransferases (KATs) and histone deacetylases (HDAC) plays a central role in neurodegeneration. In this work, we leverage the informatics infrastructure developed for TREAT‐AD, to align epigenetic regulation from two different models: the KAT5 knockout mouse and HDAC2 knockdown iPSC‐derived neurons of control and FAD genetic lineages.MethodThe KAT5 knockout mouse differential expression data derived from the CA1 of the hippocampus was compared to three groups: 1) human late onset Alzheimer’s disease (LOAD), 2) the 5X FAD mice and 3) human FAD patient transcriptomic data. In each comparison, the data was assessed in the context of the biological domains (19 core AD endophenotypes computationally defined for the TREAT‐AD bioinformatics pipeline). The KAT5 data are compared to the differential expression data derived from WT and FAD lines of iPSC‐derived neurons with or without HDAC2 knockdown (KD) post‐differentiation.ResultThe biological domain focused analysis found a consistent modulation of synaptic and immune genes across models. Interestingly, there is a statistically significant correlation between down‐regulated synaptic genes in the KAT5 knockout mouse data and human LOAD differential expression observed in the 1700 brains of transcriptomic data and 1100 brains of proteomic data analyzed for TREAT‐AD and concomitantly identified in early stage pseudotemporal models of AD. Not surprisingly, there is better correlation between the KAT5 KO mouse and the 5X FAD mice, with the human FAD data falling in between these comparisons. The examination of the FAD and WT iPSC‐derived neurons with and without HDAC2 KD, demonstrates that HDAC2 KD ameliorates the down‐regulation of synaptic genes in the FAD neurons, but appears to have the opposite effect in WT human neurons.ConclusionThe comparison of the two systems of epigenetic regulation suggest that KAT5 and HDAC2 exert opposite effects upon synaptic gene expression. However, the observation that decreasing HDAC2 levels increases synaptic gene expression in FAD neurons but decreases synaptic gene expression in normal healthy neurons suggest that there is an optimal chromatin state associated with maximal synaptic gene expression, and that too much or too little histone acetylation may impair synaptic homeostasis.