AGO CLIP Reveals an Activated Network for Acute Regulation of Brain Glutamate Homeostasis in Ischemic Stroke.
| Publication Type | Academic Article |
| Authors | Kobayashi M, Benakis C, Anderson C, Moore M, Poon C, Uekawa K, Dyke J, Fak J, Mele A, Park C, Zhou P, Anrather J, Iadecola C, Darnell R |
| Journal | Cell Rep |
| Volume | 28 |
| Issue | 4 |
| Pagination | 979-991.e6 |
| Date Published | 07/23/2019 |
| ISSN | 2211-1247 |
| Keywords | Argonaute Proteins, Brain, Brain Ischemia, Cross-Linking Reagents, Glutamic Acid, Homeostasis, Stroke |
| 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. |
| DOI | 10.1016/j.celrep.2019.06.075 |
| PubMed ID | 31340158 |
| PubMed Central ID | PMC6784548 |