Myelination of the central nervous system (CNS) by oligodendrocytes (OLs) is essential for the development and function of the CNS. Myelin develops in the CNS as OLs differentiate into the myelin-forming mature phenotype. The differentiation of OLs is under tight regulation, and its dysregulation causes neurological disorders and has been linked to neuropsychiatric diseases. Genetic studies have shown that Myrf is a key transcription factor for the development and life-long maintenance of myelin in the CNS. Recent studies have also demonstrated that Myrf is critical to the fine-tuning of myelin thickness and its plasticity that underlies learning in the adult stage. Despite these crucial role, it remains poorly understood how Myrf regulates transcription, and this significantly impedes the progress in this field. Using bioinformatics and experimental approaches, we recently made the breakthrough observations that Myrf is a membrane-bound transcription factor, and that Myrf may function as a homo-trimeric transcription factor. Membrane-bound transcription factors are generated as membrane proteins that, upon relevant stimuli, undergo proteolytic activation to release transcription factor domains from the membrane, with Notch being the most famous example. Our discovery fundamentally changes the paradigm for Myrf, providing a powerful framework to understand its functional mechanism. Building upon this discovery, Aim I will elucidate how Myrf is activated by proteolysis. The proteolytic activation of Myrf releases its N-terminal fragment from the membrane, allowing it to translocate into the nucleus for transcriptional regulation.
Aim II will determine how the N-terminal fragment of Myrf interacts with DNA as a homo-trimer for transcription. Our computational and experimental analyses indicate that functional collaboration with other transcription factors is critical to the transcriptional activity of Myrf.
Aim III will elucidate which transcription factors interact with yrf for coordinated differentiation of OLs. In sum, this study will elucidate the transcription mechanism of Myrf for OL differentiation and CNS myelination.
Myelination of the central nervous system by oligodendrocytes is essential for the development and function of the central nervous system. Impaired myelination causes neurological disorders and has also been linked to neuropsychiatric diseases. This project will elucidate the mechanism of action of Myrf, a key transcription factor for central nervous system myelination.
|Choi, Jin-Ok; Fan, Chuandong; Kim, Dongkyeong et al. (2018) Elucidating the transactivation domain of the pleiotropic transcription factor Myrf. Sci Rep 8:13075|
|Shen, Xiaomeng; Shen, Shichen; Li, Jun et al. (2017) An IonStar Experimental Strategy for MS1 Ion Current-Based Quantification Using Ultrahigh-Field Orbitrap: Reproducible, In-Depth, and Accurate Protein Measurement in Large Cohorts. J Proteome Res 16:2445-2456|
|Kim, Dongkyeong; Choi, Jin-Ok; Fan, Chuandong et al. (2017) Homo-trimerization is essential for the transcription factor function of Myrf for oligodendrocyte differentiation. Nucleic Acids Res 45:5112-5125|