N6-methyladenosine RNA modification regulates embryonic neural stem cell self-renewal through histone modifications
Internal N 6-methyladenosine (m6A) modification is widespread in messenger RNAs (mRNAs) and is catalyzed by heterodimers of methyltransferase-like protein 3 (Mettl3) and Mettl14. To understand the role of m6A in development, we deleted Mettl14 in embryonic neural stem cells (NSCs) in a mouse model....
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Science and Business Media LLC
2020
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| Online Access: | https://hdl.handle.net/1721.1/128892 |
| _version_ | 1811069838065401856 |
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| author | Wang, Yang Li, Yue Yue, Minghui Wang, Jun Wechsler-Reya, Robert J. Zhang, Zhaolei Ogawa, Yuya Kellis, Manolis Duester, Gregg Zhao, Jing Crystal |
| author2 | Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory |
| author_facet | Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory Wang, Yang Li, Yue Yue, Minghui Wang, Jun Wechsler-Reya, Robert J. Zhang, Zhaolei Ogawa, Yuya Kellis, Manolis Duester, Gregg Zhao, Jing Crystal |
| author_sort | Wang, Yang |
| collection | MIT |
| description | Internal N 6-methyladenosine (m6A) modification is widespread in messenger RNAs (mRNAs) and is catalyzed by heterodimers of methyltransferase-like protein 3 (Mettl3) and Mettl14. To understand the role of m6A in development, we deleted Mettl14 in embryonic neural stem cells (NSCs) in a mouse model. Phenotypically, NSCs lacking Mettl14 displayed markedly decreased proliferation and premature differentiation, suggesting that m6A modification enhances NSC self-renewal. Decreases in the NSC pool led to a decreased number of late-born neurons during cortical neurogenesis. Mechanistically, we discovered a genome-wide increase in specific histone modifications in Mettl14 knockout versus control NSCs. These changes correlated with altered gene expression and observed cellular phenotypes, suggesting functional significance of altered histone modifications in knockout cells. Finally, we found that m6A regulates histone modification in part by destabilizing transcripts that encode histone-modifying enzymes. Our results suggest an essential role for m6A in development and reveal m6A-regulated histone modifications as a previously unknown mechanism of gene regulation in mammalian cells. |
| first_indexed | 2024-09-23T08:17:37Z |
| format | Article |
| id | mit-1721.1/128892 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T08:17:37Z |
| publishDate | 2020 |
| publisher | Springer Science and Business Media LLC |
| record_format | dspace |
| spelling | mit-1721.1/1288922022-09-23T12:07:39Z N6-methyladenosine RNA modification regulates embryonic neural stem cell self-renewal through histone modifications Wang, Yang Li, Yue Yue, Minghui Wang, Jun Wechsler-Reya, Robert J. Zhang, Zhaolei Ogawa, Yuya Kellis, Manolis Duester, Gregg Zhao, Jing Crystal Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory Internal N 6-methyladenosine (m6A) modification is widespread in messenger RNAs (mRNAs) and is catalyzed by heterodimers of methyltransferase-like protein 3 (Mettl3) and Mettl14. To understand the role of m6A in development, we deleted Mettl14 in embryonic neural stem cells (NSCs) in a mouse model. Phenotypically, NSCs lacking Mettl14 displayed markedly decreased proliferation and premature differentiation, suggesting that m6A modification enhances NSC self-renewal. Decreases in the NSC pool led to a decreased number of late-born neurons during cortical neurogenesis. Mechanistically, we discovered a genome-wide increase in specific histone modifications in Mettl14 knockout versus control NSCs. These changes correlated with altered gene expression and observed cellular phenotypes, suggesting functional significance of altered histone modifications in knockout cells. Finally, we found that m6A regulates histone modification in part by destabilizing transcripts that encode histone-modifying enzymes. Our results suggest an essential role for m6A in development and reveal m6A-regulated histone modifications as a previously unknown mechanism of gene regulation in mammalian cells. NIH (Grants R01-MH109978, R01-HG008155, RF1-AG054012 and U01-HG007610) 2020-12-22T16:19:13Z 2020-12-22T16:19:13Z 2018-01 2017-07 2019-07-18T13:25:26Z Article http://purl.org/eprint/type/JournalArticle 1097-6256 1546-1726 https://hdl.handle.net/1721.1/128892 Wang, Yang et al. "N6-methyladenosine RNA modification regulates embryonic neural stem cell self-renewal through histone modifications." Nature Neuroscience 21, 2 (January 2018): 195–206 © 2018 The Author(s) en http://dx.doi.org/10.1038/s41593-017-0057-1 Nature Neuroscience Creative Commons Attribution 4.0 International license https://creativecommons.org/licenses/by/4.0/ application/pdf Springer Science and Business Media LLC Nature |
| spellingShingle | Wang, Yang Li, Yue Yue, Minghui Wang, Jun Wechsler-Reya, Robert J. Zhang, Zhaolei Ogawa, Yuya Kellis, Manolis Duester, Gregg Zhao, Jing Crystal N6-methyladenosine RNA modification regulates embryonic neural stem cell self-renewal through histone modifications |
| title | N6-methyladenosine RNA modification regulates embryonic neural stem cell self-renewal through histone modifications |
| title_full | N6-methyladenosine RNA modification regulates embryonic neural stem cell self-renewal through histone modifications |
| title_fullStr | N6-methyladenosine RNA modification regulates embryonic neural stem cell self-renewal through histone modifications |
| title_full_unstemmed | N6-methyladenosine RNA modification regulates embryonic neural stem cell self-renewal through histone modifications |
| title_short | N6-methyladenosine RNA modification regulates embryonic neural stem cell self-renewal through histone modifications |
| title_sort | n6 methyladenosine rna modification regulates embryonic neural stem cell self renewal through histone modifications |
| url | https://hdl.handle.net/1721.1/128892 |
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