ERRα and ERRγ coordinate expression of genes associated with Alzheimer's disease, inhibiting DKK1 to suppress tau phosphorylation

Alzheimer's disease (AD) is a prevalent neurodegenerative disease characterized by cognitive decline and learning/memory impairment associated with neuronal cell loss. Estrogen- related receptor alpha (ERR alpha) and ERR gamma, which are highly expressed in the brain, have emerged as potential AD regulators, with unelucidated underlying mechanisms. Here, we identified genome-wide binding sites for ERR alpha and ERR gamma in human neuronal cells. They commonly target a subset of genes associated with neurodegenerative diseases, including AD. Notably, Dickkopf-1 (DKK1), aWntsignalingpathwayantag- onist, was transcriptionally repressed by both ERR alpha and ERR gamma in human neuronal cells and brain. ERR alpha and ERR gamma repress RNA polymerase II (RNAP II) accessibility at the DKK1 promoter by modulating a specific active histone modification, histone H3 lysine acetylation (H3K9ac), with the potential contribution of their corepressor. This transcriptional repression maintains Wnt signaling activity, preventing tau phosphorylation and promoting a healthy neuronal state in the context of AD.