newly acquired memory becomes stable for long-term storage through a process known as memory consolidation, which requires de novo gene expression. Disruption of gene transcription during this process specifically blocks long-term memory formation. The braln-derlved neurotrophic factor (BDNF) has been shown to play an essential role in the consolidation or storage of long-term memory. However, little is known about the regulation of exon-specific ibc/nf transcripts in the brain and how this level of bdnf ger e regulation functions in the process of memory formation. The major scientific goal of this proposal is to identify epigenetic-regulating mechanisms for /bofn^gerie expression changes that serve to stabilize long-term memory. The underlying hypothesis of this grant Is that aberrant epigenetic markings such as posttranslational modification of histones, DNA methylation and transcription factor activation plays a role in exon-specific bdnf gene regulation in memory formation. The mentored phase ofthis proposal will dissect epigenetic mechanisms of exon-specific Mn?gene regulation during memory consolidation using a combination of approaches including measuring DNA methylation associated with exon-specific bdnf transcripts, using chromatin immunoprecipition (ChIP) technology to analyze levels of post-translational modification of histones, methyl CpG binding protein 2, and histone deacetylases at tiofnf promoter regions, and investigating whether DNMT inhibition alters 6c/nf exon-specific mRNA expression during memory consolidation. During the first independent phase aim ofthe project, the role for NMDA receptor (NMDA-R) activation in the epigenetic regulation ofthe bdnf gene will be analyzed using a combination of novel technologies to assess cell-type specific chromatin remodeling of M/if transcripts in hippocampus. The second Independent phase aim will evaluate the functional Impact of NMDA -R-medlated recruitment ofthe transcription factor nuclear factor kappa B (NF-KB) to /bc/nf regulatory elements within DNA and to identify the role ofthe NF-KB DNA-binding complex in the regulation of chromatin remodeling ofthe bdnf gene. This proposal explores the role of epigenetic mechanisms of bdnf ger e regulation In long-term memory formation with a focus on identifying molecular mechanisms that may lead to drug discovery and development to intervene in the ciinicai features of mental disorders. Indeed, epigenetic mechanisms have been implicated in the etiology of mental illnesses, such as schizophrenia, depression, and bipolar disorder. Through the understanding of epigenetic-regulating mechanisms involved in /bofnf gene expression during memory formation and potentially in mental disorders, other genes involved in this process may fall into a common biochemical pathway where disease intervention Is possible

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Transition Award (R00)
Project #
Application #
Study Section
Special Emphasis Panel (NSS)
Program Officer
Beckel-Mitchener, Andrea C
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Alabama Birmingham
Schools of Medicine
United States
Zip Code
Butler, Anderson A; Webb, William M; Lubin, Farah D (2016) Regulatory RNAs and control of epigenetic mechanisms: expectations for cognition and cognitive dysfunction. Epigenomics 8:135-51
Maity, Sabyasachi; Jarome, Timothy J; Blair, Jessica et al. (2016) Noradrenaline goes nuclear: epigenetic modifications during long-lasting synaptic potentiation triggered by activation of ?-adrenergic receptors. J Physiol 594:863-81
Parrish, R Ryley; Buckingham, Susan C; Mascia, Katherine L et al. (2015) Methionine increases BDNF DNA methylation and improves memory in epilepsy. Ann Clin Transl Neurol 2:401-16
Gupta-Agarwal, Swati; Jarome, Timothy J; Fernandez, Jordan et al. (2014) NMDA receptor- and ERK-dependent histone methylation changes in the lateral amygdala bidirectionally regulate fear memory formation. Learn Mem 21:351-62
Jarome, Timothy J; Lubin, Farah D (2014) Epigenetic mechanisms of memory formation and reconsolidation. Neurobiol Learn Mem 115:116-27
Jarome, Timothy J; Lubin, Farah D (2013) Histone lysine methylation: critical regulator of memory and behavior. Rev Neurosci 24:375-87
Ryley Parrish, R; Albertson, A J; Buckingham, S C et al. (2013) Status epilepticus triggers early and late alterations in brain-derived neurotrophic factor and NMDA glutamate receptor Grin2b DNA methylation levels in the hippocampus. Neuroscience 248:602-19
Parrish, R Ryley; Day, Jeremy J; Lubin, Farah D (2012) Direct bisulfite sequencing for examination of DNA methylation with gene and nucleotide resolution from brain tissues. Curr Protoc Neurosci Chapter 7:Unit 7.24
Gupta-Agarwal, Swati; Franklin, Aimee V; Deramus, Thomas et al. (2012) G9a/GLP histone lysine dimethyltransferase complex activity in the hippocampus and the entorhinal cortex is required for gene activation and silencing during memory consolidation. J Neurosci 32:5440-53
Puckett, Rosemary E; Lubin, Farah D (2011) Epigenetic mechanisms in experience-driven memory formation and behavior. Epigenomics 3:649-64

Showing the most recent 10 out of 17 publications