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<p>N6-methyladenosine (m<sup>6</sup>A) is the most prevalent RNA modification and plays diverse roles in mammalian cells. However, its significance in human trophoblast lineage commitment and placenta development remains poorly understood. Here we show that METTL3, the primary enzyme responsible for m<sup>6</sup>A depositions, specifically marks cytotrophoblasts in human placenta, and exhibits defective expression in cytotrophoblasts from preeclampsia patients. Through in-depth in vitro investigation, we identify critical roles of METTL3 in generating human trophoblast stem cells (hTSCs) from human expanded potential stem cells, and in maintaining hTSCs’ self-renewal and identity. In hTSCs, METTL3 loss induces pro-inflammatory responses and promotes premature senescence, leading to preeclampsia-associated transcriptomic signature. Mechanistically, METTL3-dependent m<sup>6</sup>A methylation directly regulates histone modifiers such as EP300 and EZH2 to maintain epigenetic homeostasis, as well as various transcription factors, including JUND. Targeted inhibition of EP300 in hTSCs successfully ameliorate preeclampsia signature caused by METTL3 deficiency. These findings reveal METTL3-dependent m<sup>6</sup>A methylation as a critical regulator of human trophoblast development and its potential involvement in pregnancy-related diseases.</p>

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METTL3 safeguards cell identity and epigenome of human trophoblast stem cells

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年12月16日

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  • Haifeng Fu,
  • Chunxiao Chen,
  • Yunying Huang,
  • Weiyu Zhang,
  • Shilong Li,
  • For-Fan Chan,
  • Ling Xu,
  • Degong Ruan,
  • Xiangyu Ouyang,
  • Liyang Ma,
  • Zhen Feng,
  • Qingqing Zhang,
  • Chunyan Wang,
  • Dai Heng,
  • Kexin Yao,
  • Asif Javed,
  • Chun-Ming Wong,
  • Yin Lau Lee,
  • William Shu Biu Yeung,
  • Baofa Sun,
  • Pentao Liu

摘要

N6-methyladenosine (m6A) is the most prevalent RNA modification and plays diverse roles in mammalian cells. However, its significance in human trophoblast lineage commitment and placenta development remains poorly understood. Here we show that METTL3, the primary enzyme responsible for m6A depositions, specifically marks cytotrophoblasts in human placenta, and exhibits defective expression in cytotrophoblasts from preeclampsia patients. Through in-depth in vitro investigation, we identify critical roles of METTL3 in generating human trophoblast stem cells (hTSCs) from human expanded potential stem cells, and in maintaining hTSCs’ self-renewal and identity. In hTSCs, METTL3 loss induces pro-inflammatory responses and promotes premature senescence, leading to preeclampsia-associated transcriptomic signature. Mechanistically, METTL3-dependent m6A methylation directly regulates histone modifiers such as EP300 and EZH2 to maintain epigenetic homeostasis, as well as various transcription factors, including JUND. Targeted inhibition of EP300 in hTSCs successfully ameliorate preeclampsia signature caused by METTL3 deficiency. These findings reveal METTL3-dependent m6A methylation as a critical regulator of human trophoblast development and its potential involvement in pregnancy-related diseases.