Adenosine Triphosphate, Animals, Calcium, Male, Mice, Mice, Inbred C57BL, MicroRNAs, Promoter Regions, Genetic, Receptors, Purinergic P2X7, Sp1 Transcription Factor, Transcription, Genetic
This work was supported by funding from Science Foundation Ireland (13/SIRG/2098 to T.E and 13/SIRG/2114 to E.M.J-M and 13/IA/1891 to D.H), from the Health Research Board (HRA-POR2015-1243 to TE), from the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement n° 602130 (to D.C.H) and from the H2020 Marie Skłowdowksa-Curie Actions Individual Fellowship (Project no. 707530) (to G.P.B.)
Cells have developed complex transcriptional regulatory mechanisms to maintain intracellular homeostasis and withstand pathophysiological stressors. Feed-forward loops comprising transcription factors that drive expression of both target gene and a microRNA as negative regulator, are gaining increasing recognition as key regulatory elements of cellular homeostasis. The ATP-gated purinergic P2X7 receptor (P2X7R) is an important driver of inflammation and has been implicated in the pathogenesis of numerous brain diseases including epilepsy. Changes in P2X7R expression have been reported in both experimental models and in epilepsy patients but the mechanism(s) controlling P2X7R levels remain incompletely understood. The specificity protein 1 (Sp1) has been shown to induce P2X7R transcription in vitro and recent data has identified microRNA-22 as a post-transcriptional repressor of P2X7R expression after seizures. In the present study we show that Sp1 can induce the transcription of both microRNA-22 and P2X7R in vitro during increased neuronal activity and in vivo in a mouse model of status epilepticus. We further show that Sp1-driven microRNA-22 transcription is calcium-sensitive and Sp1 occupancy of the microRNA-22 promoter region is blocked under conditions of seizure activity sufficient to elicit neuronal death. Taken together, our results suggest a neuronal activity-dependent P2X7R expression which is induced by the transcription factor Sp1 and repressed in a calcium-dependent manner by microRNA-22.
Physics | Physiology
Engel T,Brennan GP,Sanz-Rodriguez A,Alves M,Beamer E,Watters O,Henshall DC,Jimenez-Mateos EM. A calcium-sensitive feed-forward loop regulating the expression of the ATP-gated purinergic P2X7 receptor via specificity protein 1 and microRNA-22. Biochimica et Biophysica Acta. 2017; 1864(2):255-266
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 4.0 License.