Loss of KAT5-dependent H2A.Z acetylation provokes chromosomal instability in recurrent pregnancy loss
6 affiliations
- 1Department of Obstetrics and Gynecology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, Guangdong-Hong Kong-Macao Great Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou 510150, China.
- 2Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing 100026, China.
- 3National Institute of Biological Sciences, Beijing 102206, China.
- 4Fujian Provincial Key Laboratory of Reproductive Health Research, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, China.
- 5Obstetrics and Gynecology Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China.
- 6Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing 102206, China.
Abstract
Placenta defects are one of the major causes of miscarriages, yet the underlying mechanisms remain poorly understood. We demonstrate that trophoblast-specific depletion of the acetyltransferase Kat5, or introduction of acetylation-defective mutants Kat5-Q377E G380E and Kat5-Y47A, induces severe chromosomal instability (CIN) during trophoblast cells division, leading to embryonic lethality. Moreover, mutation of a key lysine acetyltransferase 5 (KAT5) substrate, H2A.Z, via the introduction of H2az1-K5R K8R K12R K14R (which prevents H2A.Z acetylation), phenocopies the effects of KAT5 loss. Integrated RNA sequencing and CUT&Tag in mouse trophoblast stem cells reveal that KAT5, through H2A.Z acetylation, regulates transcription of key mitotic genes (Aurka, Aurkb, and Cenpa). We extend our finding to human trophoblast stem cells, demonstrating a conserved role for KAT5 in preventing CIN. Clinical analysis of placental villi from recurrent pregnancy loss patients with copy number variations revealed reduced expression of KAT5 and acetylated H2A.Z. This study demonstrates that the conserved KAT5-H2A.Z acetylation pathway safeguards chromosomal stability in trophoblast cells, supporting placenta development and successful pregnancy.
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BibTeX
@article{bi2026loss,
title = {{Loss of KAT5-dependent H2A.Z acetylation provokes chromosomal instability in recurrent pregnancy loss}},
author = {Shilei Bi and Yongjie Chen and Lizi Zhang and Jiahui Zhang and Yijing Wang and Baoying Huang and Shanze Li and Lijun Huang and Yifan Wang and Huarong Wang and Ranran Meng and Zhaowei Tu and Lili Du and Haibin Wang and Zhijian Wang and Dunjin Chen and Shuang Zhang and Fengchao Wang},
journal = {Science Advances},
year = {2026},
month = oct,
doi = {10.1126/sciadv.aef6029},
url = {https://www.science.org/doi/10.1126/sciadv.aef6029},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Loss of KAT5-dependent H2A.Z acetylation provokes chromosomal instability in recurrent pregnancy loss
AU - Shilei Bi
AU - Yongjie Chen
AU - Lizi Zhang
AU - Jiahui Zhang
AU - Yijing Wang
AU - Baoying Huang
AU - Shanze Li
AU - Lijun Huang
AU - Yifan Wang
AU - Huarong Wang
AU - Ranran Meng
AU - Zhaowei Tu
AU - Lili Du
AU - Haibin Wang
AU - Zhijian Wang
AU - Dunjin Chen
AU - Shuang Zhang
AU - Fengchao Wang
PY - 2026
DA - 2026/10/23
JO - Science Advances
DO - 10.1126/sciadv.aef6029
UR - https://www.science.org/doi/10.1126/sciadv.aef6029
AB - Placenta defects are one of the major causes of miscarriages, yet the underlying mechanisms remain poorly understood. We demonstrate that trophoblast-specific depletion of the acetyltransferase Kat5, or introduction of acetylation-defective mutants Kat5-Q377E G380E and Kat5-Y47A, induces severe chromosomal instability (CIN) during trophoblast cells division, leading to embryonic lethality. Moreover, mutation of a key lysine acetyltransferase 5 (KAT5) substrate, H2A.Z, via the introduction of H2az1-K5R K8R K12R K14R (which prevents H2A.Z acetylation), phenocopies the effects of KAT5 loss. Integrated RNA sequencing and CUT&Tag in mouse trophoblast stem cells reveal that KAT5, through H2A.Z acetylation, regulates transcription of key mitotic genes (Aurka, Aurkb, and Cenpa). We extend our finding to human trophoblast stem cells, demonstrating a conserved role for KAT5 in preventing CIN. Clinical analysis of placental villi from recurrent pregnancy loss patients with copy number variations revealed reduced expression of KAT5 and acetylated H2A.Z. This study demonstrates that the conserved KAT5-H2A.Z acetylation pathway safeguards chromosomal stability in trophoblast cells, supporting placenta development and successful pregnancy.
SN - 2375-2548
ER -