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1.
FASEB J ; 38(13): e23706, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-38877842

RESUMO

The etiology of preeclampsia (PE), a complex and multifactorial condition, remains incompletely understood. DNA methylation, which is primarily regulated by three DNA methyltransferases (DNMTs), DNMT1, DNMT3A, and DNMT3B, plays a vital role in early embryonic development and trophectoderm differentiation. Yet, how DNMTs modulate trophoblast fusion and PE development remains unclear. In this study, we found that the DNMTs expression was downregulated during trophoblast cells fusion. Downregulation of DNMTs was observed during the reconstruction of the denuded syncytiotrophoblast (STB) layer of placental explants. Additionally, overexpression of DNMTs inhibited trophoblast fusion. Conversely, treatment with the DNA methylation inhibitor 5-aza-CdR decreased the expression of DNMTs and promoted trophoblast fusion. A combined analysis of DNA methylation data and gene transcriptome data obtained from the primary cytotrophoblasts (CTBs) fusion process identified 104 potential methylation-regulated differentially expressed genes (MeDEGs) with upregulated expression due to DNA demethylation, including CD59, TNFAIP3, SDC1, and CDK6. The transcription regulation region (TRR) of TNFAIP3 showed a hypomethylation with induction of 5-aza-CdR, which facilitated CREB recruitment and thereby participated in regulating trophoblast fusion. More importantly, clinical correlation analysis of PE showed that the abnormal increase in DNMTs may be involved in the development of PE. This study identified placental DNA methylation-regulated genes that may contribute to PE, offering a novel perspective on the role of epigenetics in trophoblast fusion and its implication in PE development.


Assuntos
DNA (Citosina-5-)-Metiltransferases , Metilação de DNA , Pré-Eclâmpsia , Trofoblastos , Trofoblastos/metabolismo , Feminino , Pré-Eclâmpsia/genética , Pré-Eclâmpsia/metabolismo , Pré-Eclâmpsia/patologia , Gravidez , Humanos , DNA (Citosina-5-)-Metiltransferases/genética , DNA (Citosina-5-)-Metiltransferases/metabolismo , Fusão Celular , Placenta/metabolismo , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , DNA (Citosina-5-)-Metiltransferase 1/genética
2.
J Cell Biochem ; 121(7): 3547-3559, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31898356

RESUMO

Oocyte apoptosis can be used as an indicator of oocyte quality and development competency. Phospholipase C (PLC) is a critical enzyme that participates in phosphoinositide metabolic regulation and performs many functions, including the regulation of reproduction. In this study, we aimed to explore whether PLC participates in the regulation of apoptosis in porcine oocytes and investigated its possible mechanism. In porcine oocytes, 0.5 µM U73122 (the PLC inhibitor) was considered to be the best concentration to facilitate maturation, and 0.5 µM m-3M3FBS (the PLC activator) was regarded as the most appropriate concentration to inhibit maturation. The percentage of cleavage and blastocysts treated with 0.5 µM U73122 was lower than that of the control group. Furthermore, the percentage of cleavage and blastocysts treated with 0.5 µM m-3M3FBS was higher than that of the control group. The relative PLC messenger RNA (mRNA) expression tested by a quantitative real-time polymerase chain reaction was found to be inhibited by 0.5 µM U73122 or activated by 0.5 µM m-3M3FBS. The relative mRNA abundance of BAK, BAX, CASP3, CASP8, and TP53 and protein abundance of Bak, cleaved caspase-3, caspase-8, and P53 was activated by U73122 or inhibited by m-3M3FBS, while the relative mRNA and protein level of BCL6 showed the opposite trend. The intracellular Ca2+ concentration increased and the expression of PLCB1 protein also increased in porcine oocytes when they were cultured with 0.5 µM m-3M3FBS for 44 hours. The abundance of proteins PKCß and CAMKIIα and the expression of several downstream genes (CDC42, NFATc1, NFATc2, NFκB, and NLK) were activated by m-3M3FBS or inhibited by U73122. Our findings indicate that PLC inhibits apoptosis and maturation in porcine oocytes. The intracellular Ca2+ concentration, two Ca2+ -sensitive proteins, and several downstream genes were positively regulated by PLC.


Assuntos
Apoptose/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento , Oócitos/efeitos dos fármacos , Fosfolipase C beta/farmacologia , Animais , Blastocisto/citologia , Cálcio/metabolismo , Núcleo Celular/metabolismo , Estrenos/farmacologia , Feminino , Perfilação da Expressão Gênica , Regulação Enzimológica da Expressão Gênica , Técnicas In Vitro , Oócitos/metabolismo , Ovário/metabolismo , Corpos Polares/metabolismo , Pirrolidinonas/farmacologia , RNA Mensageiro/metabolismo , Transdução de Sinais , Suínos
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