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1.
Heliyon ; 7(7): e07570, 2021 Jul.
Article in English | MEDLINE | ID: mdl-34377851

ABSTRACT

Brain-derived neurotrophic factor (Bdnf) expression is tightly controlled at the transcriptional and post-transcriptional levels. Previously, we showed that inhibition of noncoding Bdnf antisense (Bdnf-AS) RNA upregulates Bdnf protein. Here, we generated a Bdnf-antisense knockout (Bdnf-AS KO) mouse model by deleting 6 kilobases upstream of Bdnf-AS. After verifying suppression of Bdnf-AS, baseline behavioral tests indicated no significant difference in knockout and wild type mice, except for enhanced cognitive function in the knockout mice in the Y-maze. Following acute involuntary exercise, Bdnf-AS KO mice were re-assessed and a significant increase in Bdnf mRNA and protein were observed. Following long-term involuntary exercise, we observed a significant increase in nonspatial and spatial memory in novel object recognition and Barnes maze tests in young and aged Bdnf-AS KO mice. Our data provides evidence for the beneficial effects of endogenous Bdnf upregulation and the synergistic effect of Bdnf-AS knockout on exercise and memory retention.

2.
J Biomol Screen ; 20(9): 1132-41, 2015 Oct.
Article in English | MEDLINE | ID: mdl-26173710

ABSTRACT

Long non-protein coding RNAs (lncRNAs) are an important class of molecules that help orchestrate key cellular events. Although their functional roles in cells are not well understood, thousands of lncRNAs and a number of possible mechanisms by which they act have been reported. LncRNAs can exert their regulatory function in cells by interacting with epigenetic enzymes. In this study, we developed a tool to study lncRNA-protein interactions for high-throughput screening of small-molecule modulators using AlphaScreen technology. We tested the interaction of two lncRNAs: brain-derived neurotrophic factor antisense (BDNF-AS) and Hox transcript antisense RNA (HOTAIR), with Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase against a phytochemical library, to look for small-molecule inhibitors that can alter the expression of downstream target genes. We identified ellipticine, a compound that up-regulates BDNF transcription. Our study shows the feasibility of using high-throughput screening to identify modulators of lncRNA-protein interactions and paves the road for targeting lncRNAs that are dysregulated in human disorders using small-molecule therapies.


Subject(s)
High-Throughput Screening Assays , RNA, Long Noncoding/antagonists & inhibitors , Brain-Derived Neurotrophic Factor/biosynthesis , Brain-Derived Neurotrophic Factor/genetics , Drug Evaluation, Preclinical , Ellipticines/pharmacology , Enhancer of Zeste Homolog 2 Protein , Gene Expression/drug effects , HEK293 Cells , Humans , Polycomb Repressive Complex 2/biosynthesis , Polycomb Repressive Complex 2/genetics , Protein Binding/drug effects , RNA Interference/drug effects , RNA, Long Noncoding/biosynthesis , RNA, Long Noncoding/chemistry
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