Computational divergence analysis reveals the existence of regulatory degeneration and supports HDAC1 as a potential drug target for Alzheimer's disease

Epigenetic dysregulation has been widely reported in patients of Alzheimers disease (AD) and epigenetic drugs are gaining particular interest as a potential candidate therapy target. However, it is less clear how epigenetic dysregulation contributes to AD development. In this work, we performed regulatory divergence analysis using large-scale AD brain RNA-seq data and reported a widespread existence of regulatory degeneration among AD patients. It seems that transcription factor (TF)-mediated regulations get weakened or lost during AD development, resulting in disruption of normal neuronal function, especially including protein degradation, neuroinflammation, mitochondria and synaptic dysfunction. The regulatory degeneration burden (RDB) is well correlated with the detrimental clinical manifestations of AD patients. Studies of epigenetic marks, including histone modification, open chromatin accessibility and three TF binding sites supported the existence of regulatory degeneration. It suggested that epigenetic dysregulation contributed to regulatory degeneration, which also explained the consequence of epigenetic dysregulation. Among the epigenetic regulators, HDAC1 was proposed as a potential participator in such a process. Overall, our computational analysis suggested a novel causal mechanism of AD development and proposed HDAC1 as a drug target to treat AD.