英国剑桥大学Courtney W. Hanna等合作发现，在人类滋养层干细胞中异位表达DNMT3L可以恢复胎盘甲基组的特征。2025年1月8日出版的《细胞—干细胞》发表了这项成果。

胎盘DNA甲基化图谱是独特的，具有广泛的部分甲基化结构域（PMDs）。胎盘“甲基组”在哺乳动物中是保守的，这是许多癌症的共同特征，并被广泛研究与妊娠并发症的联系。人类滋养层干细胞（hTSCs）为更好地理解这种表观遗传特征的功能研究，提供了令人兴奋的潜力。然而，人类滋养层干细胞表观基因组是否重现初级滋养细胞仍不清楚。

研究人员发现，与滋养外胚层和妊娠早期的滋养层细胞相比，人类滋养层干细胞表现出非典型的甲基组。无论细胞来源、氧水平或培养条件如何，人类滋养层干细胞都表现出转录基因体内的局部DNA甲基化，和部分甲基化结构域的完全缺失。与早期人类滋养层细胞不同，人类滋养层干细胞明显缺乏DNMT3L的表达，而DNMT3L是在同母细胞滋养层细胞中，建立部分甲基化结构域所必需的。

值得注意的是，该研究证明了人类滋养层干细胞中DNMT3L的异位表达，可以恢复胎盘部分甲基化结构域，支持DNMT3L在人类胚胎发育时滋养层细胞发育中新生甲基化中的保守作用。

附：英文原文

Title: Ectopic expression of DNMT3L in human trophoblast stem cells restores features of the placental methylome

Author: Georgia Lea, Paula Doria-Borrell, Ana Ferrero-Micó, Anakha Varma, Claire Simon, Holly Anderson, Laura Biggins, Katrien De Clercq, Simon Andrews, Kathy K. Niakan, Lenka Gahurova, Naomi McGovern, Vicente Pérez-García, Courtney W. Hanna

Issue&Volume: 2025-01-08

Abstract: The placental DNA methylation landscape is unique, with widespread partially methylated domains (PMDs). The placental “methylome” is conserved across mammals, a shared feature of many cancers, and extensively studied for links with pregnancy complications. Human trophoblast stem cells (hTSCs) offer exciting potential for functional studies to better understand this epigenetic feature; however, whether the hTSC epigenome recapitulates primary trophoblast remains unclear. We find that hTSCs exhibit an atypical methylome compared with trophectoderm and 1st trimester cytotrophoblast. Regardless of cell origin, oxygen levels, or culture conditions, hTSCs show localized DNA methylation within transcribed gene bodies and a complete loss of PMDs. Unlike early human trophoblasts, hTSCs display a notable absence of DNMT3L expression, which is necessary for PMD establishment in mouse trophoblasts. Remarkably, we demonstrate that ectopic expression of DNMT3L in hTSCs restores placental PMDs, supporting a conserved role for DNMT3L in de novo methylation in trophoblast development in human embryogenesis.

DOI: 10.1016/j.stem.2024.12.007

Source: https://www.cell.com/cell-stem-cell/abstract/S1934-5909(24)00447-8