A substantial body of evidence suggests that many neurological diseases may commonly result from perturbations of activity-dependent changes in neural functions. During brain development, sensory stimulation-dependent modulation of individual neurons and circuits involves not only structural and functional changes in local synaptic connections, but also a cell-wide arrangement for sustained adaptive responses. Sensory experience-dependent gene expression is an integral mechanism of cell-wide adaptation as it is responsible for the stimulus-specific production and deployment of proteins with various functions in individual neurons, which are required for appropriate adaptive responses. In keeping with this notion, mutations in several genes implicated in the signaling pathways from the synapse to the nucleus have been linked to various neurological diseases such as autism and epilepsy, suggesting that the disruption of activity-dependent gene expression programs under specific circumstances, such as activity-dependent learning can elicit a pathophysiological condition. As such, the study to understand how genetic and epigenetic programs accurately translate sensory information into changes in relevant neural circuits and cognitive behavior bears clinical significance. A recent genome-wide study revealed that a novel class of long non-protein coding RNAs (lncRNAs) called eRNAs (enhancer RNAs) is rapidly expressed from thousands of neuronal enhancers when neurons are excited. The eRNA is quite unique among various types of lncRNAs in that its expression is rapid, transient, and dynamically controlled by sensory stimulation-evoked neuronal activity. The pervasive nature and strong expression correlation with nearby mRNAs suggest a provoking idea that the eRNA might be functionally implicated in the sensory stimulation-induced neural and behavioral plasticity by playing an active role in neural gene expression. Initial analysis of the eRNA function further supports this hypothesis. Given that less than 2% of the mammalian genome accounts for protein-coding genes, an increasing number of mutations associated with neurological diseases will be found to reside in the non-coding regions as human genetic studies continue to advance. The proposed study involves a multidisciplinary approach to examine the role of eRNA in activity-dependent transcription and subsequent changes in synaptic and behavioral plasticity. The eRNA-dependent epigenetic mechanism may represent a new layer of complexity in the molecular architecture of many neurological diseases.

Public Health Relevance

A growing body of evidence suggests that several neurological diseases such as autism and epilepsy may commonly result from perturbations of activity-dependent changes in neural functions. Sensory experience- induced neuronal gene expression is an integral mechanism of the cell-wide adaptation required for synaptic and behavioral plasticity, and mutations in several genes in the signaling pathways from the synapse to the nucleus have also been linked to various neurological diseases (e.g., Mecp2 for Rett Syndrome, Cbp for Rubinstein-Taybi Syndrome). Therefore, studies investigating activity-dependent gene expression programs that faithfully translate sensory information into the structural and functional changes in relevant neural circuits should provide fundamental insight into the pathophysiology of human neurological diseases.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01NS085418-02
Application #
8733776
Study Section
Molecular Neurogenetics Study Section (MNG)
Program Officer
Riddle, Robert D
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Neurosciences
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390
Kim, Seung-Kyoon; Lee, Hosuk; Han, Kyumin et al. (2014) SET7/9 methylation of the pluripotency factor LIN28A is a nucleolar localization mechanism that blocks let-7 biogenesis in human ESCs. Cell Stem Cell 15:735-49
Schaukowitch, K; Kim, T-K (2014) Emerging epigenetic mechanisms of long non-coding RNAs. Neuroscience 264:25-38
Schaukowitch, Katie; Joo, Jae-Yeol; Liu, Xihui et al. (2014) Enhancer RNA facilitates NELF release from immediate early genes. Mol Cell 56:29-42