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<p>N6-methyladenosine (m<sup>6</sup>A) 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 m<sup>6</sup>A-dependent manner. Mechanistically, we found that suppressing METTL3 and YTHDF2 prolongs the lifetimes of pluripotency-associated mRNAs, such as&#xa0;<i>Nanog</i>&#xa0;and&#xa0;<i>Sox2</i>, during PNT. In addition,&#xa0;<i>Gstp1</i>&#xa0;was identified as a downstream target of METTL3 inhibition and YTHDF2 knockout.&#xa0;<i>Gstp1</i>&#xa0;overexpression enhances PNT, whereas its inhibition impedes the transition. Overall, our findings suggest that YTHDF2 facilitates the removal of pluripotency gene transcripts and&#xa0;<i>Gstp1</i>, thereby promoting PNT reprogramming through m<sup>6</sup>A-mediated posttranscriptional control.</p>

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METTL3 inhibits primed-to-naïve transition of pluripotent stem cells through m6A-YTHDF2-pluripotency/Gstp1 mRNA degradation axis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月27日

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  • 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

摘要

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.