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AGO CLIP Reveals an Activated Network for Acute Regulation of Brain Glutamate Homeostasis in Ischemic Stroke.

TitleAGO CLIP Reveals an Activated Network for Acute Regulation of Brain Glutamate Homeostasis in Ischemic Stroke.
Publication TypeJournal Article
Year of Publication2019
AuthorsKobayashi M, Benakis C, Anderson C, Moore MJ, Poon C, Uekawa K, Dyke JP, Fak JJ, Mele A, Park CY, Zhou P, Anrather J, Iadecola C, Darnell RB
JournalCell Rep
Volume28
Issue4
Pagination979-991.e6
Date Published2019 Jul 23
ISSN2211-1247
Abstract

Post-transcriptional regulation by microRNAs (miRNAs) is essential for complex molecular responses to physiological insult and disease. Although many disease-associated miRNAs are known, their global targets and culminating network effects on pathophysiology remain poorly understood. We applied Argonaute (AGO) crosslinking immunoprecipitation (CLIP) to systematically elucidate altered miRNA-target interactions in brain following ischemia and reperfusion (I/R) injury. Among 1,190 interactions identified, the most prominent was the cumulative loss of target regulation by miR-29 family members. Integration of translational and time-course RNA profiles revealed a dynamic mode of miR-29 target de-regulation, led by acute translational activation and a later increase in RNA levels, allowing rapid proteomic changes to take effect. These functional regulatory events rely on canonical and non-canonical miR-29 binding and engage glutamate reuptake signals, such as glial glutamate transporter (GLT-1), to control local glutamate levels. These results uncover a miRNA target network that acts acutely to maintain brain homeostasis after ischemic stroke.

DOI10.1016/j.celrep.2019.06.075
Alternate JournalCell Rep
PubMed ID31340158