Neuronal enhancer RNAs (eRNAs)
Changes in the transcriptional programs of neurons or neuronal progenitors lie at the heart of neuronal plasticity and neurogenesis, respectively. Genes that regulate these processes are under the control of enhancer elements that are differentially regulated during neuronal stimulation and brain development. Enhancers are DNA sequences bound by at times multiple transcription factors. In a combinatorial activation process the combined activity of all bound factors is believed to determine the extent of target gene activation.
In addition, neuronal enhancers were recently shown to be actively transcribed, giving rise to non-coding enhancer RNAs (eRNAs). eRNAs significantly contribute to the activation of most immediate early genes (IEG) in mouse neurons. Moreover, eRNA expression levels serve as a better indicator of enhancer activity than transcription factor binding data. However, how enhancer RNAs are able to direct brain development and neuronal plasticity in vivo is unknown. In particular, it is unknown how much enhancer transcription contributes to enhancer function during these processes.
Stimulus-induced transcription activation of neuronal immediate early genes (IEGs)
We pursue the hypothesis that enhancer RNAs directly influence the RNA polymerase II (Pol II) transcription machinery by diminishing promoter-proximal pausing of important neuronal genes. To examine this hypothesis, we combine chemical mapping of RNA structure, in vitro biochemistry, next-generation sequencing and in vivo studies of zebrafish neurogenesis.
With our work we want to clarify, which role eRNAs play in regulating metazoan transcription. eRNAs may lie at the heart of tissue-specific gene expression in health and disease and they may trigger developmental decisions. Furthermore, eRNAs likely shape the neuronal networks in our brain by contributing to neuronal plasticity.
A possible competition model for the function of neuronal enhancer RNAs.
Tae-Kyung Kim, UT Southwestern Medical Center, Department of Neuroscience, Dallas, TX, USA