Reactivation of hyperglycemia-induced hypocretin (HCRT) gene silencing by N-acetyl-d-mannosamine in the orexin neurons derived from human iPS cells
| Autor: | Shusaku Daikoku, Yasuharu Sakamoto, Koji Hayakawa, Osamu Kanie, Kunio Shiota, Yukishige Ito, Atsuko Ohtake |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cancer Research medicine.medical_specialty Induced Pluripotent Stem Cells Biology Epigenesis Genetic Histones 03 medical and health sciences Histone H3 Internal medicine mental disorders medicine Gene silencing Humans Epigenetics Gene Silencing Molecular Biology Neurons Orexins Neurodegeneration Neurogenesis digestive oral and skin physiology Acetylation Hexosamines DNA Methylation medicine.disease Orexin Cell biology 030104 developmental biology Endocrinology medicine.anatomical_structure nervous system Hyperglycemia DNA methylation Neuron psychological phenomena and processes hormones hormone substitutes and hormone antagonists Research Paper |
| DOI: | 10.6084/m9.figshare.5264125 |
| Popis: | Orexin neurons regulate critical brain activities for controlling sleep, eating, emotions, and metabolism, and impaired orexin neuron function results in several neurologic disorders. Therefore, restoring normal orexin function and understanding the mechanisms of loss or impairment of orexin neurons represent important goals. As a step toward that end, we generated human orexin neurons from induced pluripotent stem cells (hiPSCs) by treatment with N-acetyl-d-mannosamine (ManNAc) and its derivatives. The generation of orexin neurons was associated with DNA hypomethylation, histone H3/H4 hyperacetylation, and hypo-O-GlcNAcylation on the HCRT gene locus, and, thereby, the treatment of inhibitors of SIRT1 and OGT were effective at inducing orexin neurons from hiPSCs. The prolonged exposure of orexin neurons to high glucose in culture caused irreversible silencing of the HCRT gene, which was characterized by H3/H4 hypoacetylation and hyper-O-GlcNAcylation. The DNA hypomethylation status, once established in orexin neurogenesis, was maintained in the HCRT-silenced orexin neurons, indicating that histone modifications, but not DNA methylation, were responsible for the HCRT silencing. Thus, the epigenetic status of the HCRT gene is unique to the hyperglycemia-induced silencing. Intriguingly, treatment of ManNAc and its derivatives reactivated HCRT gene expression, while inhibitors SIRT1 and the OGT did not. The present study revealed that the HCRT gene was silenced by the hyperglycemia condition, and ManNAc and its derivatives were useful for restoring the orexin neurons. |
| Databáze: | OpenAIRE |
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