METTL3 inhibits primed-to-naïve transition of pluripotent stem cells through m6A-YTHDF2-pluripotency/Gstp1 mRNA degradation axis
Abstract N6-methyladenosine (m6A) plays crucial roles in development and cellular reprogramming. During embryonic development, pluripotency transitions from a naïve to a primed state, and modeling the reverse primed-to-naïve transition (PNT) provides a valuable framework for investigating pluripoten...
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| Format: | Article |
| Language: | English |
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SpringerOpen
2025-05-01
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| Series: | Cell Regeneration |
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| Online Access: | https://doi.org/10.1186/s13619-025-00241-1 |
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| author | Sa Li Jiajie Hao Guangliang Hong Hongzhi Dong He Liu Lingmei Jin Zhihao Zhang Haoyu Wu Mingli Hu Rujin Huang Guanzheng Luo Jiangping He Jiekai Chen Kaixin Wu |
| author_facet | Sa Li Jiajie Hao Guangliang Hong Hongzhi Dong He Liu Lingmei Jin Zhihao Zhang Haoyu Wu Mingli Hu Rujin Huang Guanzheng Luo Jiangping He Jiekai Chen Kaixin Wu |
| author_sort | Sa Li |
| collection | DOAJ |
| description | Abstract N6-methyladenosine (m6A) plays crucial roles in development and cellular reprogramming. During embryonic development, pluripotency transitions from a naïve to a primed state, and modeling the reverse primed-to-naïve transition (PNT) provides a valuable framework for investigating pluripotency regulation. Here, we show that inhibiting METTL3 significantly promotes PNT in an m6A-dependent manner. Mechanistically, we found that suppressing METTL3 and YTHDF2 prolongs the lifetimes of pluripotency-associated mRNAs, such as Nanog and Sox2, during PNT. In addition, Gstp1 was identified as a downstream target of METTL3 inhibition and YTHDF2 knockout. Gstp1 overexpression enhances PNT, whereas its inhibition impedes the transition. Overall, our findings suggest that YTHDF2 facilitates the removal of pluripotency gene transcripts and Gstp1, thereby promoting PNT reprogramming through m6A-mediated posttranscriptional control. |
| format | Article |
| id | doaj-art-1d8fea516f524dd78d36796341cab231 |
| institution | OA Journals |
| issn | 2045-9769 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | SpringerOpen |
| record_format | Article |
| series | Cell Regeneration |
| spelling | doaj-art-1d8fea516f524dd78d36796341cab2312025-08-20T02:00:12ZengSpringerOpenCell Regeneration2045-97692025-05-0114111510.1186/s13619-025-00241-1METTL3 inhibits primed-to-naïve transition of pluripotent stem cells through m6A-YTHDF2-pluripotency/Gstp1 mRNA degradation axisSa Li0Jiajie Hao1Guangliang Hong2Hongzhi Dong3He Liu4Lingmei Jin5Zhihao Zhang6Haoyu Wu7Mingli Hu8Rujin Huang9Guanzheng Luo10Jiangping He11Jiekai Chen12Kaixin Wu13Center for Biomedical Digital Science, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of SciencesCenter for Biomedical Digital Science, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of SciencesGuangzhou LaboratoryCenter for Biomedical Digital Science, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of SciencesCenter for Biomedical Digital Science, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of SciencesCenter for Biomedical Digital Science, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of SciencesMOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen UniversityCenter for Biomedical Digital Science, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of SciencesCenter for Biomedical Digital Science, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of SciencesGuangzhou LaboratoryMOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen UniversityGuangzhou LaboratoryCenter for Biomedical Digital Science, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of SciencesSchool of Life Sciences, Precise Genome Engineering Center, Guangzhou UniversityAbstract N6-methyladenosine (m6A) plays crucial roles in development and cellular reprogramming. During embryonic development, pluripotency transitions from a naïve to a primed state, and modeling the reverse primed-to-naïve transition (PNT) provides a valuable framework for investigating pluripotency regulation. Here, we show that inhibiting METTL3 significantly promotes PNT in an m6A-dependent manner. Mechanistically, we found that suppressing METTL3 and YTHDF2 prolongs the lifetimes of pluripotency-associated mRNAs, such as Nanog and Sox2, during PNT. In addition, Gstp1 was identified as a downstream target of METTL3 inhibition and YTHDF2 knockout. Gstp1 overexpression enhances PNT, whereas its inhibition impedes the transition. Overall, our findings suggest that YTHDF2 facilitates the removal of pluripotency gene transcripts and Gstp1, thereby promoting PNT reprogramming through m6A-mediated posttranscriptional control.https://doi.org/10.1186/s13619-025-00241-1METTL3Primed to Naïve TransitionYTHDF2Gstp1 |
| spellingShingle | Sa Li Jiajie Hao Guangliang Hong Hongzhi Dong He Liu Lingmei Jin Zhihao Zhang Haoyu Wu Mingli Hu Rujin Huang Guanzheng Luo Jiangping He Jiekai Chen Kaixin Wu METTL3 inhibits primed-to-naïve transition of pluripotent stem cells through m6A-YTHDF2-pluripotency/Gstp1 mRNA degradation axis Cell Regeneration METTL3 Primed to Naïve Transition YTHDF2 Gstp1 |
| title | METTL3 inhibits primed-to-naïve transition of pluripotent stem cells through m6A-YTHDF2-pluripotency/Gstp1 mRNA degradation axis |
| title_full | METTL3 inhibits primed-to-naïve transition of pluripotent stem cells through m6A-YTHDF2-pluripotency/Gstp1 mRNA degradation axis |
| title_fullStr | METTL3 inhibits primed-to-naïve transition of pluripotent stem cells through m6A-YTHDF2-pluripotency/Gstp1 mRNA degradation axis |
| title_full_unstemmed | METTL3 inhibits primed-to-naïve transition of pluripotent stem cells through m6A-YTHDF2-pluripotency/Gstp1 mRNA degradation axis |
| title_short | METTL3 inhibits primed-to-naïve transition of pluripotent stem cells through m6A-YTHDF2-pluripotency/Gstp1 mRNA degradation axis |
| title_sort | mettl3 inhibits primed to naive transition of pluripotent stem cells through m6a ythdf2 pluripotency gstp1 mrna degradation axis |
| topic | METTL3 Primed to Naïve Transition YTHDF2 Gstp1 |
| url | https://doi.org/10.1186/s13619-025-00241-1 |
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