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- Differentiation of trophoblast stem (TS) cells or progenitor cytotrophoblasts (CTBs) into multinucleated syncytiotrophoblasts (STBs) is essential for placental development. Disruption of this process contributes to major obstetrical syndromes, including fetal growth restriction and preeclampsia, and Trisomy 21. However, the chromatin mechanisms governing trophoblast stemness and differentiation remain inadequately defined. Here we identify the chromatin-associated factor PHF13, uncovered through a high-throughput microRNA target screen, as a key regulator of trophoblast cell fate. PHF13 knockout TS cells exhibited defects that ultimately resulted in loss of cell viability, whereas PHF13 knockdown promoted expression of fusion-associated genes, including ERVFRD-1 and human chorionic gonadotropin (hCG). Consistently, PHF13 depletion in BeWo trophoblast cells increased hCG expression and secretion while reducing expression of canonical stemness-associated transcription factors ELF5 and TEAD4. Integrated genomic analyses further revealed that PHF13 target genes comprise a gene regulatory network that maintains trophoblast stemness and restrains differentiation. Notably, the pluripotency-associated transcription factor THAP11 partially co-occupies genomic sites with PHF13. Together, these findings establish PHF13 as a previously unrecognized chromatin regulator of trophoblast stemness and differentiation, providing mechanistic insight into pathways critical for placental development and function. - Source: PubMed
Publication date: 2026/03/17
Liu ShengLiu LeiMeng JiayuSadovsky ElenaHuang KeyiSorenson HeatherChu TianjiaoSadovsky YoelOuyang Yingshi - : Immune checkpoint inhibitor (ICI)-based combinations have significantly improved outcomes in metastatic clear cell renal cell carcinoma (mccRCC). However, a substantial number of patients fail to derive clinical benefit, highlighting the need for reliable predictive biomarkers. Circulating biomarkers represent an attractive, non-invasive alternative to tissue-based assays. This study aimed to evaluate the immunity-related genes and as potential blood-based candidate biomarkers associated with response to ICI-based therapy in mccRCC. : Peripheral blood samples were collected prior to treatment initiation from 34 patients with mccRCC receiving PD-1-based therapy. Gene expression levels of and were quantified using real-time PCR. Treatment response was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Peripheral blood samples from healthy individuals were included as controls. : Both and were significantly dysregulated in mccRCC patients compared with healthy controls. Their expression differed between patients with clinical benefit and those with progressive disease. Specifically, patients with progressive disease exhibited reduced expression and increased expression compared with patients showing clinical benefit. : and were associated with treatment response in this pilot cohort and may represent promising blood-based biomarker candidates, requiring validation in larger prospective multicenter studies. - Source: PubMed
Publication date: 2026/02/23
Katifelis HectorZerva Styliani-EvangeliaBamias AristotelisKaramouzis Michalis VStravodimos KonstantinosSechi Leonardo ALampropoulou Dimitra-IoannaPliakou EvangeliaGazouli Maria - Syncytin-2 is an endogenous retroviral envelope protein constitutively expressed in human placental trophoblasts. As a membrane glycoprotein, Syncytin-2 together with Syncytin-1 mediates the fusion of mononucleated cytotrophoblasts to form multinucleated syncytiotrophoblasts. Syncytiotrophoblasts constitute the fetal-maternal interface important for fetal-maternal exchange, barrier and endocrine functions of the placenta. Besides the fusogenic function, Syncytin-2 also possesses an immunosuppressive activity. In this study, the results of quantitative PCR indicated that Syncytin-2 expression was downregulated in third-trimester preeclamptic placentas, which is consistent with the result of previous studies. Importantly, the results of Combined Bisulfite Restriction Assay (COBRA) suggested hypermethylation of the downstream CpG-rich region, but not the promoter/exon1/intron1 and exon2 CpG- rich regions of SYN-2 gene in third-trimester preeclamptic placentas. Subsequent bisulfite conversion and PCR amplification, cloning and sequencing of the downstream CpG- rich region confirmed hypermethylation of the 4 CpGs in this region in preeclamptic placentas. Moreover, treatment of human choriocarcinoma BeWo cells with DNMT inhibitor ADC (5-aza-deoxycytidine) resulted in a dose-responsive demethylation of the downstream CpG-rich region and an increased SYN-2 mRNA level. Thus, the hypermethylation of the downstream CpG-rich region closely correlated with the downregulation of Syncytin-2 expression in preeclamptic placentas. These new findings underscore the significance of epigenetic alterations in preeclamptic placentas, and facilitate a better understanding on the pathological mechanism of preeclampsia. - Source: PubMed
Publication date: 2025/12/03
Feng ChunZhang TengLi YuanLong YuyunMeng QianJiang Shi-Wen - Abnormal expression levels of microRNAs are associated with numerous diseases in the female reproductive tract. A small subset of human endogenous retroviruses (HERVs) genes have retained open reading frames (ORFs) that serve beneficial functions for the host. Syncytin-1 (HERV-W) and Syncytin-2 (HERV-FRD) play crucial roles in mammalian development and are expressed in placental trophoblasts. The miRNAs associated with HERV-W and HERV-FRD in spontaneous abortion and endometriosis have not been elucidated. The present study aimed to identify potential miRNAs that affect the regulation of Syncytin-1 and Syncytin-2 in endometriosis and miscarriage using bioinformatics tools. Complete CDS of Syncytin-1 (ERVW-1) and Syncytin-2 (ERVFRD-1) genes were collected from the gene bank database. Several target prediction algorithms were utilized, such as TargetScan, DIANA, miRDB, and miRWalk. Complete CDS of Syncytin-1 (ERVW-1) and Syncytin-2 (ERVFRD-1) genes were collected from the gene bank database. By integrating data from these diverse bioinformatics databases, miR-509-3p and miR-625-5p were consistent across multiple platforms, ensuring robust selection criteria. These tools facilitate the identification of differentially expressed miRNAs, understanding their roles in cellular processes, and potentially utilizing them as biomarkers for disease diagnosis and prognosis. Validation of the identified miRNAs in experimental models or clinical samples is needed to confirm their roles in endometriosis and miscarriage. - Source: PubMed
Gholami-Barzoki MehdiShatizadeh-Malekshahi SomayehShayestehpour MohammadSoltanghoraee Haleh - Suppressyn, a placenta-specific protein characterized by its inhibitory effect on trophoblast cell fusion, is considered to play a direct role in the formation and maintenance of placental villi in humans. Given the potential involvement of aberrant suppressyn expression in the development of placenta-dependent disorders, we focused our analysis on hypertensive disorders of pregnancy, with particular emphasis on preeclampsia (PE). PE is a leading cause of maternal morbidity and mortality worldwide and poses a serious risk to fetal growth and survival. As delivery remains the only definitive treatment and no effective methods for prevention or early diagnosis have been established, there is an urgent need for investigation from novel perspectives. In the present study, we investigated the expression profiles of suppressyn and fusion-associated molecules in human placental villous tissues and maternal blood samples. Our analysis revealed two key findings: (1) suppressyn protein levels are significantly reduced in placentas from pregnancies complicated by PE with fetal growth restriction (FGR), and (2) suppressyn secretion is modulated in an ASCT2 expression-dependent manner, suggesting that the intracellular balance between suppressyn and this transporter may play a critical role in the pathophysiology of PE and in maintaining placental function. Detectable alterations in maternal serum concentrations of secreted suppressyn in pregnancies affected by hypertensive disorders of pregnancy may offer a novel biomarker that monitors placental developmental status in these disease states. These findings may also provide new insights into the molecular underpinnings of PE and a mechanistic link between suppressyn dysregulation and the development of FGR. - Source: PubMed
Publication date: 2025/11/03
Sugimoto JunSchust Danny JNagamatsu TakeshiYano ErikoSugimoto MakikoYamazaki TomomiKudo Yoshiki