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

Mariko Kobayashi; Corinne Benakis; Corey J. 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

doi:10.1016/j.celrep.2019.06.075

Molecular BiologyCell ReportsJul 1, 2019

Peer-reviewed journal article

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

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

Abstract

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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