Lineage-specific and gestational age–dependent DNA methylation programming orchestrates human placental development
4 affiliations
- 1Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Signal Transduction and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
- 2Frontier Science Center for Stem Cell Research, Tongji University, Shanghai 200092, China.
- 3Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of the Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200065, China.
- 4Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai 201204, China.
Abstract
The human placenta is essential for pregnancy, yet the dynamic regulation of its DNA methylome during development remains poorly understood. To address this, we generated a single base-resolution DNA methylation atlas of human placental trophoblasts across gestation. We identified a lineage-specific methylation program established immediately after implantation, followed by gestational age-dependent methylation accumulation. This program acted as a developmental barrier that coordinated placental maturation and immune homeostasis. By integrating histone modifications and functional perturbations, we revealed a temporal dynamic between H3K27me3 and DNA methylation that silenced proinflammatory loci and a switch from H3K9me3 to DNA methylation at repeat elements to maintain genome stability. Aberrant methylation in preterm placentas underscored the physiological importance of methylation regulation. Using human trophoblast stem cells, we demonstrated that DNMT1 was critically required for maintaining trophoblast methylome integrity and self-renewal, while the DNMT3 family were equally essential for trophoblast survival. Overall, we established a placenta-specific epigenetic framework for human trophoblast development.
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BibTeX
@article{yi2026lineagespecific,
title = {{Lineage-specific and gestational age–dependent DNA methylation programming orchestrates human placental development}},
author = {Shanru Yi and Jing Xiao and Ruixue Wang and Mengting Wang and Chunyan Le and Guang Yang and Shanshan Yi and Wenju Liu and Hong Wang and Xiaocui Li and Xiaoyu Liu and Kai Wang and Cizhong Jiang and Shaorong Gao and Jiayu Chen},
journal = {Science Advances},
year = {2026},
month = oct,
doi = {10.1126/sciadv.aee0560},
url = {https://www.science.org/doi/10.1126/sciadv.aee0560},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Lineage-specific and gestational age–dependent DNA methylation programming orchestrates human placental development
AU - Shanru Yi
AU - Jing Xiao
AU - Ruixue Wang
AU - Mengting Wang
AU - Chunyan Le
AU - Guang Yang
AU - Shanshan Yi
AU - Wenju Liu
AU - Hong Wang
AU - Xiaocui Li
AU - Xiaoyu Liu
AU - Kai Wang
AU - Cizhong Jiang
AU - Shaorong Gao
AU - Jiayu Chen
PY - 2026
DA - 2026/10/23
JO - Science Advances
DO - 10.1126/sciadv.aee0560
UR - https://www.science.org/doi/10.1126/sciadv.aee0560
AB - The human placenta is essential for pregnancy, yet the dynamic regulation of its DNA methylome during development remains poorly understood. To address this, we generated a single base-resolution DNA methylation atlas of human placental trophoblasts across gestation. We identified a lineage-specific methylation program established immediately after implantation, followed by gestational age-dependent methylation accumulation. This program acted as a developmental barrier that coordinated placental maturation and immune homeostasis. By integrating histone modifications and functional perturbations, we revealed a temporal dynamic between H3K27me3 and DNA methylation that silenced proinflammatory loci and a switch from H3K9me3 to DNA methylation at repeat elements to maintain genome stability. Aberrant methylation in preterm placentas underscored the physiological importance of methylation regulation. Using human trophoblast stem cells, we demonstrated that DNMT1 was critically required for maintaining trophoblast methylome integrity and self-renewal, while the DNMT3 family were equally essential for trophoblast survival. Overall, we established a placenta-specific epigenetic framework for human trophoblast development.
SN - 2375-2548
ER -