同济大学高亚威课题组的最新研究揭示了L1PA上的N6-甲基腺苷控制LTRs的反式沉默并抑制幼稚人胚胎干细胞的全能性。2025年10月29日，国际知名学术期刊《细胞—干细胞》发表了这一成果。

研究小组证明，甲基转移酶样3缺陷使未成熟的人胚胎干细胞（hESCs）恢复到全能样状态，8C相关基因、eRNAs和LTRs，特别是ERV1和ERV1-MaLR的再激活和染色质重置。

此外，还发现灵长类特异性L1PA上的m⁶A是必不可少的。在机制上，L1PA结合8C相关的LTRs和eRNA，并通过带有染色质调节剂的RNA-支架复合物调节染色质，其中m⁶A指导蛋白质结合偏好。在初始hESCs中，L1PA上的m⁶A抑制EP300与ERV1的结合，增强KAP1与ERV1-MaLR的结合，从而限制LTR的活性。同时，m⁶A- l1pa轴或eRNA上的m⁶A将EP300/H3K27ac的占用限制在8C增强子。他们的发现揭示了一种保守的机制，即人类和小鼠利用具有m⁶A的物种特异性长穿插核元件-1亚家族来调节LTR活性，强调了转座子在细胞命运转变过程中RNA-染色质串扰中的关键作用。

研究人员表示，转座因子（TEs）占据了基因组的近一半，并推动了发育创新，但其沉默长末端重复序列（LTRs）的机制仍未完全了解。

附：英文原文

Title: N6-methyladenosine on L1PA governs the trans-silencing of LTRs and restrains totipotency in naive human embryonic stem cells

Author: Xuehao Zhu, Zhanhe Chang, Weide Xiao, Xinbao Zhang, Mingli Ma, Jiang Wu, Jindian Hu, Yan Bi, Xiaochen Kou, Yanhong Zhao, Yifan Sheng, Baoxing Dong, Jiaxing Sun, Che Chen, You Wu, Xuelian Liu, Wenqing Ding, Kaiyuan Jia, Yingfan Yao, Lihua Sun, Xianbin Yu, Hong Wang, Jun Liu, Yixuan Wang, Shaorong Gao, Yawei Gao

Issue&Volume: 2025-10-29

Abstract: Transposable elements (TEs) occupy nearly half of the genome and drive developmental innovation, yet the mechanisms of silencing long terminal repeats (LTRs) remain incompletely understood. We demonstrate that methyltransferase-like 3 deficiency reverts naive human embryonic stem cells (hESCs) to a totipotent-like state with reactivation and chromatin resetting of 8C-associated genes, eRNAs, and LTRs, particularly ERV1 and ERVL-MaLR. Moreover, m6A on primate-specific L1PA is found to be essential. Mechanistically, L1PA binds 8C-associated LTRs and eRNAs and regulates chromatin through RNA-scaffold complexes with chromatin regulators, where m6A directs protein-binding preference. In naive hESCs, m6A on L1PA suppresses EP300 binding to ERV1 and enhances KAP1 binding to ERVL-MaLR, thereby restricting LTR activity. In parallel, the m6A-L1PA axis or m6A on eRNAs limits EP300/H3K27ac occupancy at 8C enhancers. Our findings reveal a conserved mechanism in which humans and mice employ species-specific long interspersed nuclear element-1 subfamilies with m6A to regulate LTR activity, underscoring the crucial role of transposons in RNA-chromatin crosstalk during cell fate transitions.

DOI: 10.1016/j.stem.2025.10.003

Source: https://www.cell.com/cell-stem-cell/abstract/S1934-5909(25)00371-6