Kaili Liu
Yue Sun
Ying Cao
Jing Yang
1 State Key Laboratory of Membrane Biology, Peking University, Beijing 100871, China;
2 IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China;
3 Center for Life Sciences, Peking University, Beijing 100871, China;
4 School of Life Sciences, Peking University, Beijing 100871, China;
5 Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China;
6 School of Medicine, Tsinghua University, Beijing 100084, China
Funds: This study has been supported by State Key Laboratory of Membrane Biology, IDG/McGovern Institute for Brain Research, Center for Life Sciences and School of Life Sciences at Peking University, and National Natural Science Foundation of China to J. Yang (Grant Nos. 31522024 and 31771111).
Received Date: 2018-09-04
Rev Recd Date:2018-10-31
Abstract
Abstract
Microglial activation occurs in divergent neuropathological conditions. Such microglial event has the key involvement in the progression of CNS diseases. However, the transcriptional mechanism governing microglial activation remains poorly understood. Here, we investigate the microglial response to traumatic injuryinduced neurodegeneration by the 3D fluorescence imaging technique. We show that transcription factors IRF8 and PU.1 are both indispensible for microglial activation, as their specific post-developmental deletion in microglia abolishes the process. Mechanistically, we reveal that IRF8 and PU.1 directly target the gene transcription of each other in a positive feedback to sustain their highly enhanced expression during microglial activation. Moreover, IRF8 and PU.1 dictate the microglial response by cooperatively acting through the composite IRF-ETS motifs that are specifically enriched on microglial activation-related genes. This action of cooperative transcription can be further verified biochemically by the synergetic binding of IRF8 and PU.1 proteins to the composite-motif DNA. Our study has therefore elucidated the central transcriptional mechanism of microglial activation in response to neurodegenerative condition.Keywords: microglia,
3D fluorescence imaging technique,
neurodegeneration,
IRF8,
PU.1
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