title: A calcium-sensitive feed-forward loop regulating the expression of the ATP-gated purinergic P2X7 receptor via specificity protein 1 and microRNA-22.
abstract: 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.
authors.affiliation: Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland. Electronic address: tengel@rcsi.ie.
authors.forename: Tobias
authors.initials: T
authors.lastname: Engel
authors.affiliation: Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
authors.forename: Gary P
authors.initials: GP
authors.lastname: Brennan
authors.affiliation: Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
authors.forename: Amaya
authors.initials: A
authors.lastname: Sanz-Rodriguez
authors.affiliation: Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
authors.forename: Mariana
authors.initials: M
authors.lastname: Alves
authors.affiliation: Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
authors.forename: Edward
authors.initials: E
authors.lastname: Beamer
authors.affiliation: Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
authors.forename: Orla
authors.initials: O
authors.lastname: Watters
authors.affiliation: Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
authors.forename: David C
authors.initials: DC
authors.lastname: Henshall
authors.affiliation: Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
authors.forename: Eva M
authors.initials: EM
authors.lastname: Jimenez-Mateos
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D058486:Receptors, Purinergic P2X7 / Q000235:genetics / Q000502:physiology*; D016329:Sp1 Transcription Factor / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology
chemical_list: D035683:MicroRNAs; C574876:Mirn22 microRNA, mouse; D058486:Receptors, Purinergic P2X7; D016329:Sp1 Transcription Factor; D000255:Adenosine Triphosphate; D002118:Calcium
keywords: Epilepsy; Feed-forward loop; MicroRNA-22; Purinergic P2X7 receptor; Seizures; Specificity protein 1 transcription factor