Title | AGO CLIP Reveals an Activated Network for Acute Regulation of Brain Glutamate Homeostasis in Ischemic Stroke. |
Publication Type | Journal Article |
Year of Publication | 2019 |
Authors | Kobayashi 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 |
Journal | Cell Rep |
Volume | 28 |
Issue | 4 |
Pagination | 979-991.e6 |
Date Published | 2019 07 23 |
ISSN | 2211-1247 |
Keywords | Animals, Argonaute Proteins, Base Sequence, Brain, Brain Ischemia, Cross-Linking Reagents, Down-Regulation, Gene Regulatory Networks, Glucose, Glutamic Acid, Homeostasis, Humans, Immunoprecipitation, Mice, Inbred C57BL, MicroRNAs, Models, Biological, Neuroglia, Oxygen, Polymorphism, Genetic, Signal Transduction, Stroke, Time Factors |
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 |
Alternate Journal | Cell Rep |
PubMed ID | 31340158 |
PubMed Central ID | PMC6784548 |
Grant List | R01 NS081706 / NS / NINDS NIH HHS / United States R01 NS081179 / NS / NINDS NIH HHS / United States R01 NS034179 / NS / NINDS NIH HHS / United States UM1 HG008901 / HG / NHGRI NIH HHS / United States R01 NS034389 / NS / NINDS NIH HHS / United States R35 NS097404 / NS / NINDS NIH HHS / United States R56 NS034389 / NS / NINDS NIH HHS / United States R37 NS034179 / NS / NINDS NIH HHS / United States R01 NS067078 / NS / NINDS NIH HHS / United States / HHMI / Howard Hughes Medical Institute / United States |
Related Institute:
MRI Research Institute (MRIRI)