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AGO CLIP reveals an activated network for acute regulation of brain glutamate homeostasis after ischemic stroke

By Mariko Kobayashi, Corinne Benakis, Corey Anderson, Michael J Moore, Carrie Poon, Ken Uekawa, Jonathan P Dyke, John J Fak, Aldo Mele, Christopher Y. Park, Ping Zhou, Josef Anrather, Costantino Iadecola, Robert B. Darnell

Posted 10 Jan 2018
bioRxiv DOI: 10.1101/245928 (published DOI: 10.1016/j.celrep.2019.06.075)

Post-transcriptional regulation by 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 AGO CLIP to systematically elucidate altered miRNA-target interactions in brain following ischemia/reperfusion (I/R) injury. Among 1,190 identified, 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 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 to control local glutamate levels. These results uncover a miRNA target network that acts acutely to maintain brain homeostasis after ischemic stroke.

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