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Histone Acetyltransferase KAT14 Mediates CDH5 to Regulate Spiral Artery Remodeling in Preeclampsia via Cooperation
Linna Ma1, Yueying Gao2, Qina He1
1Key Laboratory of Reproductive Health Diseases Research and Translation of Ministry of Education and Key Laboratory of Human Reproductive Medicine and Genetic Research of Hainan Province and Hainan Provincial Clinical Research Center for Thalassemia, The First Affiliated Hospital of Hainan Medical University, Hainan Medical University, Haikou, China (L.M., Q.H., Y.W., J.L., F.S., Y.M.).
Background:
Preeclampsia is a severe pregnancy-related disease. Aberrant remodeling of maternal spiral arteries is one of the core pathological hallmarks. However, the precise molecular mechanisms remain unclear.
Methods:
Public databases were used to analyze histone modifications associated with preeclampsia, and histone acetyltransferase KAT14 (lysine acetyltransferase 14) was identified. Next, we assessed KAT14 expression across gestation and in preeclamptic placentas. Stable overexpression and knockout cell lines of KAT14 were constructed in HTR-8/SVneo and JEG3 cells to assess proliferation, migration, invasion, and angiogenesis in vitro and in vivo. Bulk RNA sequencing, coimmunoprecipitation, EMSA, luciferase reporter assays, chromatin immunoprecipitation, and a conditional knockout mouse model were performed to study the role of KAT14 and serum response factor in jointly regulating CDH5 and their impact on spiral artery remodeling.
Results:
We identified KAT14 as a key regulator of trophoblast cell proliferation, migration, invasion, and the placental spiral arteries. Trophoblast-specific knockout of KAT14 (mediated by CYP19A1) presented phenotypes resembling preeclampsia, including elevated blood pressure and proteinuria. The placenta was thinned, and the vascular network was abnormal. RNA sequencing identified significant CDH5 downregulation, and its overexpression effectively rescued the phenotypes in KAT14-deficient mice. Furthermore, CDH5-Cre; KAT14 knockout mice displayed high fetal mortality and defective spiral artery remodeling. Mechanistically, KAT14 acetylates histones H3K9 and H3K18, facilitating transcription factor serum response factor binding to activate CDH5 expression.
Conclusions:
Our study identifies KAT14 as a critical epigenetic regulator of placental spiral artery remodeling involved in preeclampsia. These findings provide novel mechanistic insights into the disease pathogenesis and identify KAT14 as a potential therapeutic target.
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