Epigenetic correction of defective plasticity in a tauopathy mouse model with an acetyltransferase activator [RNA-Seq]. Mus musculus

In the adult brain, histone acetylation is associated with activity-regulated transcriptional changes that are required for synaptic plasticity and memory. These processes are dismantled in neurodegenerative diseases. Here, we demonstrate that synaptic plasticity and memory deficiencies can be restored in a mouse model of tauopathy following treatment with CSP-TTK21, a small molecule activator of CBP/p300 histone acetyltransferases (HAT). CSP-TTK21 normalized the H2B acetylation levels in many genes, including a series of super-enhancer –regulated genes, associated with plasticity and neuronal function in resting tauopathic mice. CSP-TTK21 re-established part of the learning-induced hippocampal transcriptome, including the induction of immediate early genes and memory-related genes, and the down-regulation of neuronal identity genes that bear super-enhancers. This study is the first to provide in vivo proof-of-concept evidence that direct activation of CBP/p300 HAT efficiently and selectively reverses epigenetic, transcriptional, synaptic plasticity, and behavioral deficits associated to Alzheimer’s disease lesions in mice. Overall design: RNA profiles by deep sequencing using Illumina HiSeq 2500 obtained from Dorsal Hippocampus of WT and THY-Tau22 mice, not treated or treated with either Saline (S), CSP (C) ors CSP-TTK21 (T), in basal (resting, no training) or behavior (spatial training) conditions, as noted.