Low abundance noncoding antisense RNAs are transcribed from the opposite strand of many genomic loci. These endogenous regulatory elements are shown to regulate corresponding mRNA expression, in some cases through the recruitment of epigenetic enzymes that induce locus-specific chromatin modifications. Inhibition or removal of this subset of antisense transcripts leads to locus-specific up-regulation of sense mRNA and functional protein. We found that brain-derived neurotrophic factor (BDNF) is under the regulatory control of antisense RNAs that transcriptionally suppress the expression of sense mRNA and protein. The main goal of this proposal is to study the role of noncoding RNAs as epigenetic modulators of BDNF expression. Initially, we will study the mechanism of antisense RNA-mediated regulation of BDNF, in vitro, in primary cultures of human and mouse neuroepithelial cells. We will then develop tools to quantitatively measure the interaction between BDNF antisense RNA (BDNF- AS) and the epigenetic enzyme EZH2 to investigate the structural and/or sequence requirements of this interaction. Lastly, we will examine the in vivo effects of Bdnf-AS knockdown on the Bdnf locus, utilizing a mouse model of Rett syndrome (Mecp2 null mice). Studies planned under this proposal will shed light on the molecular mechanisms by which noncoding antisense RNAs, in particular BDNF-AS, regulate expression at the BDNF locus. Our unique approach will lead to identification of the molecular underpinning of noncoding RNA- protein interactions. Finally, we will study the in vivo regulatory role of endogenous BDNF-AS in a mouse model of Rett syndrome. Overall these projects will pave the road for future epigenetic studies on other genomic loci, serving to establish novel noncoding RNA therapeutic targets for several neuropsychological disorders.

Public Health Relevance

We found that brain-derived neurotrophic factor (BDNF) is under the regulatory control of antisense RNAs that suppress the expression of sense mRNA and protein. This project is to investigate the role of noncoding RNAs as epigenetic modulators of BDNF expression. This study will elucidate the molecular mechanisms underpinning antisense RNA-induced chromatin modifications.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS081208-03
Application #
8792878
Study Section
Molecular Neurogenetics Study Section (MNG)
Program Officer
Mamounas, Laura
Project Start
2013-03-01
Project End
2017-12-31
Budget Start
2015-01-01
Budget End
2015-12-31
Support Year
3
Fiscal Year
2015
Total Cost
$334,688
Indirect Cost
$115,938
Name
University of Miami School of Medicine
Department
Psychiatry
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
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