lncRNA Neat1 drives neuronal histone methylation and age-related memory impairments

Abstract

Histone methylation is critical for the formation and maintenance of long-term memories. Long noncoding RNAs (lncRNAs) are regulators of histone methyltransferases and other chromatin modifying enzymes (CMEs). We investigated how lncRNA Neat1-mediated histone methylation contributes to hippocampus-dependent long-term memory formation, using a combination of transcriptomics, RNA binding protein immunoprecipitation, CRISPR mediated gene activation, and behavioral approaches. Suppression of the lncRNA Neat1 revealed widespread changes in gene transcription as well as perturbations of histone 3 lysine 9 dimethylation (H3K9me2), a repressive histone modification mark that is dysregulated in the aging hippocampus. We identified a Neat1-dependent mechanism of transcriptional repression via H3K9me2 at the c-Fos promoter corresponding with observed changes in c-Fos mRNA levels. Overexpression of hippocampal Neat1 via CRISPRa is sufficient to impair memory formation in young adults, recapitulating observed memory deficits in old adults, while Neat1 suppression in both young and old adult mice improves memory. These results suggest that lncRNA Neat1 is a potent epigenetic regulator of hippocampus-dependent long-term memory formation.