Reactivation of hyperglycemia-induced hypocretin (HCRT) gene silencing by N-acetyl-d-mannosamine in the orexin neurons derived from human iPS cells
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...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2017-09-01
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| Series: | Epigenetics |
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| Online Access: | http://dx.doi.org/10.1080/15592294.2017.1346775 |
| _version_ | 1797678995409469440 |
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| author | Koji Hayakawa Yasuharu Sakamoto Osamu Kanie Atsuko Ohtake Shusaku Daikoku Yukishige Ito Kunio Shiota |
| author_facet | Koji Hayakawa Yasuharu Sakamoto Osamu Kanie Atsuko Ohtake Shusaku Daikoku Yukishige Ito Kunio Shiota |
| author_sort | Koji Hayakawa |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T23:07:58Z |
| format | Article |
| id | doaj.art-f861fc56c87a4904b0731cd8dcc00d7f |
| institution | Directory Open Access Journal |
| issn | 1559-2294 1559-2308 |
| language | English |
| last_indexed | 2024-03-11T23:07:58Z |
| publishDate | 2017-09-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Epigenetics |
| spelling | doaj.art-f861fc56c87a4904b0731cd8dcc00d7f2023-09-21T12:43:13ZengTaylor & Francis GroupEpigenetics1559-22941559-23082017-09-0112976477810.1080/15592294.2017.13467751346775Reactivation of hyperglycemia-induced hypocretin (HCRT) gene silencing by N-acetyl-d-mannosamine in the orexin neurons derived from human iPS cellsKoji Hayakawa0Yasuharu Sakamoto1Osamu Kanie2Atsuko Ohtake3Shusaku Daikoku4Yukishige Ito5Kunio Shiota6The University of TokyoRIKENJapan Science and Technology Agency ERATO Glycotrilogy ProjectJapan Science and Technology Agency ERATO Glycotrilogy ProjectJapan Science and Technology Agency ERATO Glycotrilogy ProjectRIKENThe University of TokyoOrexin 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.http://dx.doi.org/10.1080/15592294.2017.1346775histone acetylationhyperglycemianeurodegenerationorexino-glcnacylation |
| spellingShingle | Koji Hayakawa Yasuharu Sakamoto Osamu Kanie Atsuko Ohtake Shusaku Daikoku Yukishige Ito Kunio Shiota Reactivation of hyperglycemia-induced hypocretin (HCRT) gene silencing by N-acetyl-d-mannosamine in the orexin neurons derived from human iPS cells Epigenetics histone acetylation hyperglycemia neurodegeneration orexin o-glcnacylation |
| title | Reactivation of hyperglycemia-induced hypocretin (HCRT) gene silencing by N-acetyl-d-mannosamine in the orexin neurons derived from human iPS cells |
| title_full | Reactivation of hyperglycemia-induced hypocretin (HCRT) gene silencing by N-acetyl-d-mannosamine in the orexin neurons derived from human iPS cells |
| title_fullStr | Reactivation of hyperglycemia-induced hypocretin (HCRT) gene silencing by N-acetyl-d-mannosamine in the orexin neurons derived from human iPS cells |
| title_full_unstemmed | Reactivation of hyperglycemia-induced hypocretin (HCRT) gene silencing by N-acetyl-d-mannosamine in the orexin neurons derived from human iPS cells |
| title_short | Reactivation of hyperglycemia-induced hypocretin (HCRT) gene silencing by N-acetyl-d-mannosamine in the orexin neurons derived from human iPS cells |
| title_sort | reactivation of hyperglycemia induced hypocretin hcrt gene silencing by n acetyl d mannosamine in the orexin neurons derived from human ips cells |
| topic | histone acetylation hyperglycemia neurodegeneration orexin o-glcnacylation |
| url | http://dx.doi.org/10.1080/15592294.2017.1346775 |
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