Abstract
Transcription of immediate early genes (IEGs) in neurons is highly sensitive to neuronal activity, but the mechanism underlying these early transcription events is largely unknown. We found that several IEGs, such as Arc (also known as Arg3.1), are poised for near-instantaneous transcription by the stalling of RNA polymerase II (Pol II) just downstream of the transcription start site in rat neurons. Depletion through RNA interference of negative elongation factor, a mediator of Pol II stalling, reduced the Pol II occupancy of the Arc promoter and compromised the rapid induction of Arc and other IEGs. In contrast, reduction of Pol II stalling did not prevent transcription of IEGs that were expressed later and largely lacked promoter-proximal Pol II stalling. Together, our data strongly indicate that the rapid induction of neuronal IEGs requires poised Pol II and suggest a role for this mechanism in a wide variety of transcription-dependent processes, including learning and memory.
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Acknowledgements
We thank D. Armstrong, P. Wade and members of the Dudek laboratory for critical review of the manuscript, the National Institute of Environmental Health Sciences (NIEHS) Viral Vector Core for lentivirus preparations, the NIEHS Microarray Core for generating, processing and analyzing microarray data, the US National Institutes of Health Intramural Sequencing Center for ChIP-seq sample preparations and sequencing, and the NIEHS Imaging Center for assistance with confocal imaging. This research was supported by the Intramural Research Program of the US National Institutes of Health, NIEHS (Z01 ES100221 to S.M.D. and Z01 ES101987 to K.A.).
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R.N.S. and S.M.D. conceived and designed the study. Experiments were conducted by R.N.S., E.R.B., E.M.W., M.Z., J.-y.H., J.D.F. and K.R.D. Data analysis was performed by R.N.S., E.R.B., E.M.W. and M.Z. Bioinformatics analyses were performed by D.C.F. K.A. provided statistical analyses and technical and conceptual advice. R.N.S. and S.M.D. wrote the manuscript with input from E.M.W., E.R.B., D.C.F. and K.A.
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Saha, R., Wissink, E., Bailey, E. et al. Rapid activity-induced transcription of Arc and other IEGs relies on poised RNA polymerase II. Nat Neurosci 14, 848–856 (2011). https://doi.org/10.1038/nn.2839
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DOI: https://doi.org/10.1038/nn.2839
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