Long noncoding RNA-directed epigenetic regulation of gene expression is associated with anxiety-like behavior in mice

Spadaro, Paola A., Flavell, Charlotte R., Widagdo, Jocelyn, Ratnu, Vikram S., Troup, Michael, Ragan, Chikako, Mattick, John S. and Bredy, Timothy W. (2015) Long noncoding RNA-directed epigenetic regulation of gene expression is associated with anxiety-like behavior in mice. Biological Psychiatry, 78 12: 848-859. doi:10.1016/j.biopsych.2015.02.004

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Author Spadaro, Paola A.
Flavell, Charlotte R.
Widagdo, Jocelyn
Ratnu, Vikram S.
Troup, Michael
Ragan, Chikako
Mattick, John S.
Bredy, Timothy W.
Title Long noncoding RNA-directed epigenetic regulation of gene expression is associated with anxiety-like behavior in mice
Journal name Biological Psychiatry   Check publisher's open access policy
ISSN 1873-2402
Publication date 2015-01-01
Year available 2015
Sub-type Article (original research)
DOI 10.1016/j.biopsych.2015.02.004
Open Access Status File (Author Post-print)
Volume 78
Issue 12
Start page 848
End page 859
Total pages 12
Place of publication Philadelphia, PA, United States
Publisher Elsevier
Collection year 2016
Language eng
Formatted 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.
Keyword Anxiety
Noncoding RNA
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Queensland Brain Institute Publications
Official 2016 Collection
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Citation counts: TR Web of Science Citation Count  Cited 17 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 19 times in Scopus Article | Citations
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