Research ArticleNeuroepigenetics

Long noncoding RNA NEAT1 mediates neuronal histone methylation and age-related memory impairment

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Science Signaling  02 Jul 2019:
Vol. 12, Issue 588, eaaw9277
DOI: 10.1126/scisignal.aaw9277

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On memory and aging

It is an unfortunate aspect of aging that memory tends to decline. Butler et al. identified one way by which that happens. Using mice, mouse hippocampal neurons, and stem cell–derived human neurons, the authors found that the long noncoding RNA NEAT1—which is more commonly associated with cancer—was present in greater amounts in the aged hippocampus and facilitated histone methylation that suppressed the expression of c-FOS, a critical memory-associated gene. Depleting NEAT1 in old mice improved their performance in memory-associated behavior tests, whereas overexpressing NEAT1 in the hippocampus of younger mice impaired performance. These findings reveal a lncRNA-regulated epigenetic mechanism that contributes to age-associated cognitive impairment.

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), thereby epigenetically modifying gene expression. Here, we investigated how the lncRNA NEAT1 may epigenetically contribute to hippocampus-dependent, long-term memory formation using a combination of transcriptomics, RNA-binding protein immunoprecipitation, CRISPR-mediated gene activation (CRISPRa), and behavioral approaches. Knockdown 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 was increased in the hippocampus of aging rodents. We identified a NEAT1-dependent mechanism of transcriptional repression by H3K9me2 at the c-Fos promoter, corresponding with observed changes in c-Fos mRNA expression. Overexpression of hippocampal NEAT1 using CRISPRa was sufficient to impair memory formation in young adult mice, recapitulating observed memory deficits in old adult mice, whereas knocking down NEAT1 in both young and old adult mice improved behavior test–associated memory. These results suggest that the lncRNA NEAT1 is an epigenetic suppressor of hippocampus-dependent, long-term memory formation.

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