K-Lysine acetyltransferase 2a regulates a hippocampal gene expression network linked to memory formation

Neuronal histone acetylation has been linked to memory consolidation, and targeting histone acetylation has emerged as a promising therapeutic strategy for neuropsychiatric diseases. However, the role of histone-modifying enzymes in the adult brain is still far from being understood. Here we use RNA sequencing to screen the levels of all known histone acetyltransferases (HATs) in the hippocampal CA1 region and find that K-acetyltransferase 2a (Kat2a) - a HAT that has not been studied for its role in memory function so far - shows highest expression. Mice that lack Kat2a show impaired hippocampal synaptic plasticity and long-term memory consolidation. We furthermore show that Kat2a regulates a highly interconnected hippocampal gene expression network linked to neuroactive receptor signaling via a mechanism that involves nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). In conclusion, our data establish Kat2a as a novel and essential regulator of hippocampal memory consolidation. Synopsis The histone acetyltransferase KAT2A is a novel key regulator of hippocampal memory consolidation in mice, controlling gene expression linked to neuroactive ligand-receptor signaling in association with NF-κB. KAT2A is the most highly expressed HAT in the hippocampal CA1 region KAT2A is required for memory function KAT2A regulates a gene expression program linked to neuroactive receptor signaling. KAT2A regulates hippocampal gene expression via a mechanisms that involves acetylation of NF-κB The histone acetyltransferase KAT2A emerges as a novel key regulator of hippocampal memory consolidation in mice, controlling gene expression linked to neuroactive ligand-receptor signaling in association with NF-κB.