All ETDs from UAB

Advisory Committee Chair

Farah D Lubin

Advisory Committee Members

Lori L McMahon

Kazutoshi Nakazawa

Nicole C Riddle

Liou Y Sun

Document Type

Dissertation

Date of Award

2019

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

The post-translational modification of histones regulates gene expression and is critical for the formation and maintenance of hippocampus-dependent long-term memories. Changes in gene-specific expression of various epigenetic marks during the aging pro-cess are sufficiently consistent as to be used as an aging landmark or epigenetic clock in both humans and other species; however, the molecular mechanisms which govern the application of these marks aging are poorly explored. Recently, long noncoding RNAs (lncRNAs) have been implicated as regulators of histone methyltransferases and other chromatin-modifying enzymes (CMEs). Despite the relevance of such mechanisms to both aging and memory formation, the behavioral relevance of lncRNA-mediated histone methylation remains obscure in the hippocampus. In my dissertation research, I have examined the aging hippocampus for evidence of disrupted epigenetic marks that might explain the commonly observed age-related impairment in hippocampus-dependent memory formation. I observed dysregulation of the histone 3 lysine 9 di-methylation mark (H3K9me2) and uncovered a role for the aging-regulated lncRNA Neat1 in regulating H3K9me2 in the context of hippocampus-dependent long-term memory formation. Using an informatics approach, I have identified neuronal genes under the regulatory control of the age-related lncRNA Neat1, including the immediate early gene (IEG) c-Fos. Suppression of the lncRNA Neat1 in cultured neuronal cells re-vealed widespread changes in gene expression as well as perturbations of histone 3 lysine 9 dimethylation (H3K9me2), a repressive histone modification that I observed to be dysregulated in the aging hippocampus. Focusing on the epigenetic landscape proximal to c-Fos, I observed site-specific H3K9me2 changes corresponding with observed changes in c-Fos transcript abundance. In addition to epigenetic regulation of the memory-permissive gene c-Fos, we observed that Neat1 expression bidirectionally controls rodent performance in contextual fear conditioning, where mimicking age-related increases in hippocampal Neat1 expression was sufficient to impair memory, while suppression of Neat1 in both young and old mice was sufficient to improve memory. These results imply that the aging-induced lncRNA Neat1 is a potent molecular brake on hippocampus-dependent long-term memory formation, and suggest that epigenetic dysregulation in the hippocampus may be driven by chronic alterations in the transcription of noncoding RNAs.

Share

COinS