Long Noncoding RNA-Directed Epigenetic Regulation of Gene Expression Is Associated With Anxiety-like Behavior in Mice.

Abstract

BACKGROUND:

RNA-directed regulation of epigenetic processes has recently emerged as an important feature of mammalian differentiation and development. Perturbation of this regulatory system in the brain may contribute to the development of neuropsychiatric disorders.

METHODS:

RNA sequencing was used to identify changes in the experience-dependent expression of long noncoding RNAs (lncRNAs) within the medial prefrontal cortex of adult mice. Transcripts were validated by real-time quantitative polymerase chain reaction and a candidate lncRNA, Gomafu, was selected for further investigation. The functional role of this schizophrenia-related lncRNA was explored in vivo by antisense oligonucleotide-mediated gene knockdown in the medial prefrontal cortex, followed by behavioral training and assessment of fear-related anxiety. Long noncoding RNA-directed epigenetic regulation of gene expression was investigated by chromatin and RNA immunoprecipitation assays.

RESULTS:

RNA sequencing analysis revealed changes in the expression of a significant number of genes related to neural plasticity and stress, as well as the dynamic regulation of lncRNAs. In particular, we detected a significant downregulation of Gomafu lncRNA. Our results revealed that Gomafu plays a role in mediating anxiety-like behavior and suggest that this may occur through an interaction with a key member of the polycomb repressive complex 1, BMI1, which regulates the expression of the schizophrenia-related gene beta crystallin (Crybb1). We also demonstrated a novel role for Crybb1 in mediating fear-induced anxiety-like behavior.

CONCLUSIONS:

Experience-dependent expression of lncRNAs plays an important role in the epigenetic regulation of adaptive behavior, and the perturbation of Gomafu may be related to anxiety and the development of neuropsychiatric disorders.

• Authors: Paola A Spadaro, Charlotte R Flavell, Jocelyn Widagdo, Vikram S Ratnu, Michael Troup, Chikako Ragan, John S Mattick, Timothy W Bredy
• Journal: Biological psychiatry (Biol Psychiatry) Vol. 78 Issue 12 Pg. 848-59 (Dec 15 2015) ISSN: 1873-2402 [Electronic] United States
• PMID: 25792222 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Chemical References

• Brain-Derived Neurotrophic Factor
• Carrier Proteins
• Crybb1 protein, mouse
• Crystallins
• Homer Scaffolding Proteins
• Polycomb-Group Proteins
• RNA, Long Noncoding
• RNA, Messenger
• beta-Crystallin B Chain

Topics

• Animals
• Anxiety (genetics, metabolism, physiopathology)
• Brain-Derived Neurotrophic Factor (metabolism)
• Carrier Proteins (metabolism)
• Cells, Cultured
• Conditioning, Classical (physiology)
• Crystallins (metabolism)
• Epigenesis, Genetic
• Fear (physiology)
• Gene Expression Profiling
• Homer Scaffolding Proteins
• Male
• Mice
• Mice, Inbred C57BL
• Polycomb-Group Proteins (metabolism)
• Prefrontal Cortex (metabolism)
• Promoter Regions, Genetic
• RNA, Long Noncoding (genetics, metabolism)
• RNA, Messenger (metabolism)
• beta-Crystallin B Chain