Downregulation of CDC42 inhibits the proliferation and stemness of human trophoblast stem cell via EZRIN/YAP inactivation

Bi, Sheng; Zhang, Lizi; Huang, Lijun; Ma, Wanyun; Meng, Nan; Deng, Wei; Li, Yulian; Liang, Yingyu; Huang, Minshan; Xu, Peng; Liu, Mingxing; Chen, Jingsi; Tu, Zhaowei; Wang, Zhijian; Wang, Haibin; Lu, Jinhua; Chen, Dunjin; Du, Lili

doi:10.1007/s00441-022-03653-6

Cited by 5 publications

(4 citation statements)

References 36 publications

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“…Protein extraction, protein concentration determination, and Western blot analysis were performed following previously established protocols 46 . Briefly, tissues or cells were lysed on ice for 20 min using protein lysis buffer (Beyotime, P0013) supplemented with protease inhibitors (Roche).…”

Section: Methodsmentioning

confidence: 99%

KAT8-mediated H4K16ac is essential for sustaining trophoblast self-renewal and proliferation via regulating CDX2

Bi,

Huang,

Chen

et al. 2024

Nat Commun

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Abnormal trophoblast self-renewal and differentiation during early gestation is the major cause of miscarriage, yet the underlying regulatory mechanisms remain elusive. Here, we show that trophoblast specific deletion of Kat8, a MYST family histone acetyltransferase, leads to extraembryonic ectoderm abnormalities and embryonic lethality. Employing RNA-seq and CUT&Tag analyses on trophoblast stem cells (TSCs), we further discover that KAT8 regulates the transcriptional activation of the trophoblast stemness marker, CDX2, via acetylating H4K16. Remarkably, CDX2 overexpression partially rescues the defects arising from Kat8 knockout. Moreover, increasing H4K16ac via using deacetylase SIRT1 inhibitor, EX527, restores CDX2 levels and promoted placental development. Clinical analysis shows reduced KAT8, CDX2 and H4K16ac expression are associated with recurrent pregnancy loss (RPL). Trophoblast organoids derived from these patients exhibit impaired TSC self-renewal and growth, which are significantly ameliorated with EX527 treatment. These findings suggest the therapeutic potential of targeting the KAT8-H4K16ac-CDX2 axis for mitigating RPL, shedding light on early gestational abnormalities.

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Section: Methodsmentioning

confidence: 99%

KAT8-mediated H4K16ac is essential for sustaining trophoblast self-renewal and proliferation via regulating CDX2

Bi,

Huang,

Chen

et al. 2024

Nat Commun

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“…Research has revealed that the expression of CDC42 is significantly decreased in the villi tissue of recurrent spontaneous abortion (RSA) patients. The human trophoblast stem cells (hTSCs) model revealed a key role of CDC42 in controlling stemness and proliferation in hTSCs, which is mediated by ezrin to activate YAP in the nucleus ( Shilei et al, 2022 ).…”

Section: The Biological Function Of Ezrin In the Female Reproductive ...mentioning

confidence: 99%

“…It was observed that the expression of cyclin D1 and β-hCG in human trophoblast stem cells that had been depleted of CDC42 could be rescued by the overexpression of ezrin-T567D, an active form of ezrin that regulates membrane tension. All theses evidence suggests that CDC42/ezrin (T567) signaling is essential for YAP to be transported to the nucleus during the initial phases of placental formation ( Shilei et al, 2022 ). Taken together, Studies of phosphorylation sites may offer a novel therapeutic target for diseases.…”

Section: The Post-translational Modifications Of Ezrinmentioning

confidence: 99%

Ezrin expression in female reproductive tissues: A review of regulation and pathophysiological implications

Shi²,

Xu³

et al. 2023

Front. Cell Dev. Biol.

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Ezrin, a plasma membrane-microfilament linker, is a cytoskeletal organizer involved in many cellular activities by binding to the membrane protein-ezrin-cytoskeletal protein complex and regulating downstream signal transduction. Increasing evidence demonstrates that ezrin plays an important role in regulating cell polarity, proliferation and invasion. In this study, we analyzed the effects of ezrin on oocytes, follicle development, embryo development and embryo implantation. We reviewed the recent studies on the modalities of ezrin regulation and its involvement in the biological processes of female reproductive physiology and summarized the current research advances in ezrin inhibitors. These studies will provide new strategies and insights for the treatment of diseases.

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“…These model systems have considerably increased our possibilities to study human first-trimester placenta development in vitro. Recent studies have already reported some important regulatory pathways that control trophoblast proliferation and differentiation ( 8 – 17 ), yet our understanding of these processes remains limited.…”

mentioning

confidence: 99%

EP300 facilitates human trophoblast stem cell differentiation

van Voorden,

Keijser,

Veenboer

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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Early placenta development involves cytotrophoblast differentiation into extravillous trophoblast (EVT) and syncytiotrophoblast (STB). Defective trophoblast development and function may result in severe pregnancy complications, including fetal growth restriction and pre-eclampsia. The incidence of these complications is increased in pregnancies of fetuses affected by Rubinstein–Taybi syndrome, a developmental disorder predominantly caused by heterozygous mutations in CREB-binding protein ( CREBBP ) or E1A-binding protein p300 ( EP300 ). Although the acetyltransferases CREBBP and EP300 are paralogs with many overlapping functions, the increased incidence of pregnancy complications is specific for EP300 mutations. We hypothesized that these complications have their origin in early placentation and that EP300 is involved in that process. Therefore, we investigated the role of EP300 and CREBBP in trophoblast differentiation, using human trophoblast stem cells (TSCs) and trophoblast organoids. We found that pharmacological CREBBP/EP300 inhibition blocks differentiation of TSCs into both EVT and STB lineages, and results in an expansion of TSC-like cells under differentiation-inducing conditions. Specific targeting by RNA interference or CRISPR/Cas9-mediated mutagenesis demonstrated that knockdown of EP300 but not CREBBP, inhibits trophoblast differentiation, consistent with the complications seen in Rubinstein–Taybi syndrome pregnancies. By transcriptome sequencing, we identified transforming growth factor alpha (TGFA, encoding TGF-α) as being strongly upregulated upon EP300 knockdown. Moreover, supplementing differentiation medium with TGF-α, which is a ligand for the epidermal growth factor receptor (EGFR), likewise affected trophoblast differentiation and resulted in increased TSC-like cell proliferation. These findings suggest that EP300 facilitates trophoblast differentiation by interfering with at least EGFR signaling, pointing towards a crucial role for EP300 in early human placentation.

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Downregulation of CDC42 inhibits the proliferation and stemness of human trophoblast stem cell via EZRIN/YAP inactivation

Cited by 5 publications

References 36 publications

KAT8-mediated H4K16ac is essential for sustaining trophoblast self-renewal and proliferation via regulating CDX2

KAT8-mediated H4K16ac is essential for sustaining trophoblast self-renewal and proliferation via regulating CDX2

Ezrin expression in female reproductive tissues: A review of regulation and pathophysiological implications

EP300 facilitates human trophoblast stem cell differentiation

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