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 #
1R01NS081208-01A1
Application #
8529123
Study Section
Molecular Neurogenetics Study Section (MNG)
Program Officer
Mamounas, Laura
Project Start
2013-03-01
Project End
2017-12-31
Budget Start
2013-03-01
Budget End
2013-12-31
Support Year
1
Fiscal Year
2013
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
Velmeshev, Dmitry; Lally, Patrick; Magistri, Marco et al. (2016) CANEapp: a user-friendly application for automated next generation transcriptomic data analysis. BMC Genomics 17:49
Magistri, Marco; Velmeshev, Dmitry; Makhmutova, Madina et al. (2016) The BET-Bromodomain Inhibitor JQ1 Reduces Inflammation and Tau Phosphorylation at Ser396 in the Brain of the 3xTg Model of Alzheimer's Disease. Curr Alzheimer Res 13:985-95
Magistri, Marco; Khoury, Nathalie; Mazza, Emilia Maria Cristina et al. (2016) A comparative transcriptomic analysis of astrocytes differentiation from human neural progenitor cells. Eur J Neurosci 44:2858-2870
St Laurent, Georges; Wahlestedt, Claes; Kapranov, Philipp (2015) The Landscape of long noncoding RNA classification. Trends Genet 31:239-51
Magistri, Marco; Velmeshev, Dmitry; Makhmutova, Madina et al. (2015) Transcriptomics Profiling of Alzheimer's Disease Reveal Neurovascular Defects, Altered Amyloid-β Homeostasis, and Deregulated Expression of Long Noncoding RNAs. J Alzheimers Dis 48:647-65
Yamanaka, Yasunari; Faghihi, Mohammad Ali; Magistri, Marco et al. (2015) Antisense RNA controls LRP1 Sense transcript expression through interaction with a chromatin-associated protein, HMGB2. Cell Rep 11:967-76
Pedram Fatemi, Roya; Salah-Uddin, Sultan; Modarresi, Farzaneh et al. (2015) Screening for Small-Molecule Modulators of Long Noncoding RNA-Protein Interactions Using AlphaScreen. J Biomol Screen 20:1132-41
Fatemi, Roya Pedram; Velmeshev, Dmitry; Faghihi, Mohammad Ali (2014) De-repressing LncRNA-Targeted Genes to Upregulate Gene Expression: Focus on Small Molecule Therapeutics. Mol Ther Nucleic Acids 3:e196
Velmeshev, Dmitry; Magistri, Marco; Faghihi, Mohammad Ali (2013) Expression of non-protein-coding antisense RNAs in genomic regions related to autism spectrum disorders. Mol Autism 4:32