Molecular human reproduction最新文献

{"title":"Deconvolution of DNA methylation data reveals cell type-specific epigenomic signatures in endometriosis and eutopic endometrium.","authors":"Yucheng Wang, Patricia A Shaw, Camille K Boufford, Ashley C Davis, Elizabeth Lewis, Amanda Vallon, Lucas Tavares Naief, Michaela Ednie, Laken Ritzert, Francis R G Amrit, Nicole M Donnellan, Tianjiao Chu, Chris G McKennan, David G Peters","doi":"10.1093/molehr/gaaf061","DOIUrl":"10.1093/molehr/gaaf061","url":null,"abstract":"<p><p>Endometriosis (EM) is a debilitating disease involving the growth of endometrial glands and stroma outside the uterus. To further our understanding of epigenomic dysregulation in EM and search for disease biomarkers, we performed a comprehensive evaluation of DNA methylation in eutopic endometrium (EE) and EM lesions. We undertook deconvolution analysis of DNA methylation data previously generated from endometrial aspirate biopsies obtained from 637 EM cases and 347 controls using microarray-based DNA methylation analysis. We further analyzed DNA methylation in EM lesions and paired EE samples via solution phase hybridization and DNA sequencing. For analysis of microarray data, we used a reference-free approach (BCconf) to recover latent factors and found high correlation with EM status, suggesting EE cell proportions vary between EM cases and controls. Deconvolution revealed that epithelial cells (P-value = 9.1 × 10-3) and fibroblasts (P-value = 0.022) were reduced in EM cases. Deconvolution of the sequencing data identified differences between EM lesions and EE of cases and controls, including vascular endothelial cells (false discovery rate [FDR]-adjusted P-value = 6.1 × 10-3; more abundant in EM lesions), natural killer cells (FDR-adjusted P-value = 0.031; less abundant in EM lesions) and ovarian/endometrial epithelium (FDR-adjusted P-value = 3.2 × 10-3). We detected significant differences in cell type proportion between EE samples of cases and controls. Improved reference data for deconvolution to inform more intelligent region targeting approaches will provide further insight into the molecular phenotype of EM and may inform novel approaches for minimally invasive detection.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12809533/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145810685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MRP4 transporter is involved in the acquisition of human sperm's fertilizing ability.","authors":"Sofia Río, Tomás J Steeman, Cristian Dotto, Camila Arroyo-Salvo, María Eugenia Bogetti, Clara I Marín-Briggiler, Agustín Yaneff, Carlos A I Alonso, Gabriela Arenas, Gastón Rey Valzacchi, Dafne Magalí Silberman, Carlos A Davio, Darío Krapf, Silvina Perez-Martinez","doi":"10.1093/molehr/gaaf060","DOIUrl":"10.1093/molehr/gaaf060","url":null,"abstract":"<p><p>Cyclic AMP (cAMP) regulates multiple aspects of sperm function essential for attaining fertilizing ability; therefore, its intracellular levels must be tightly controlled to ensure proper signaling dynamics. In recent years, multidrug resistance-associated protein 4 (MRP4) has emerged as a novel regulator of cAMP homeostasis by facilitating its efflux. Previous studies from our laboratory have identified MRP4 in mammalian sperm and demonstrated its role in capacitation-associated events in murine and bovine species. However, its relevance in human sperm remains unknown. Our study demonstrates a functional MRP4 in human sperm, as its pharmacological inhibition led to a rapid (5 min) intracellular cAMP accumulation and a subsequent decrease in extracellular levels (30 min) under capacitating conditions, as assessed by radio binding protein assay. At the biological level, MRP4 inhibition resulted in a decrease in tyrosine phosphorylation at 360 min of capacitation. Membrane hyperpolarization was also affected, diminishing the induced acrosome reaction. Moreover, a significant reduction in intracellular Ca2+ levels was observed, leading to a significant decrease in progressive and total motility, as well as an inhibition of hyperactivation. In addition, our results indicated that the decrease in Ca2+ levels was due to impaired CatSper channel activity upon MRP4 inhibition. These findings suggest that MRP4-mediated cAMP efflux is essential for proper sperm function, playing a critical role in maintaining nucleotide homeostasis, which is a key determinant in the regulation of human sperm capacitation.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145804967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic, microbial, and pharmacological stimuli elicit distinct lipidomic and cytokine responses in the human placenta.","authors":"Fiona Kumnova, Oleksandr Kozlov, Eva Cifkova, Eva Trckova, Alba Gonzalez, Michaela Medkova, Nida Cavdarbasha, Cilia Abad, Miroslav Lisa, Lukas Cerveny, Frantisek Staud, Rona Karahoda","doi":"10.1093/molehr/gaag016","DOIUrl":"10.1093/molehr/gaag016","url":null,"abstract":"<p><p>The placenta integrates metabolic and immune functions essential for fetal development, and disruptions in lipid metabolism and inflammatory signaling have been implicated in pregnancy complications such as gestational diabetes mellitus (GDM), infection-associated inflammation, and preterm birth. To examine how distinct clinically relevant stressors shape these processes, we investigated placental explant responses to three representative exposures. These included high glucose (metabolic stress relevant to diabetes/GDM), lipopolysaccharide (LPS; microbial-inflammatory stress relevant to infection/chorioamnionitis), and metformin (pharmacological exposure in treated pregnancies). Human term placental explants were cultured under controlled ex vivo conditions and exposed to these stimuli. Lipidomic profiling was performed using supercritical fluid chromatography-mass spectrometry (SFC-MS), and inflammatory responses were assessed at gene, protein, and cytokine levels by qRT-PCR, western blotting, and ELISA. Explants preserved the lipid complexity of intact placenta and secreted defined lipid species, including free fatty acids, phospholipids, and sterols, indicating selective export. High glucose induced only modest cytokine responses, suggesting that acute exposure alone is insufficient for robust inflammasome activation. In contrast, LPS triggered pronounced lipid remodeling with consistent ceramide accumulation, alongside strong upregulation of interleukin 1 beta (IL1B), interleukin 6 (IL6), and tumor necrosis factor alpha (TNF) transcripts and protein release, supporting a role for ceramides in innate immune activation. Metformin displayed modest downregulation of inflammatory transcripts and lipid remodeling under basal conditions but paradoxical potentiation of LPS-induced cytokine release. These findings show that human placental explants retain key metabolic and immune functions and reveal distinct stimulus-specific signatures, offering insight into placental adaptation to metabolic, microbial, and pharmacological stressors relevant to pregnancy complications.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13016871/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147377649","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fertilization failure assay identifies stage-specific arrests in couples with total fertilization failure.","authors":"Jing Dai, Yueren Wu, Jianfang Che, Shuoping Zhang, Yifan Gu, Fei Gong, Can Dai, Ge Lin","doi":"10.1093/molehr/gaaf059","DOIUrl":"10.1093/molehr/gaaf059","url":null,"abstract":"<p><p>Fertilization is the process by which sperm and oocyte recognize each other and fuse to form a zygote. Fertilization failure is a common issue encountered in ART. However, clinically, there is a lack of identification of the specific stage at which fertilization is arrested and the development of personalized improvement strategies. In this study, we conducted a fertilization failure assay (FFA) in a cohort of 445 couples undergoing IVF (n = 394) and ICSI (n = 51) who experienced total fertilization failure (TFF). In subsequent cycles, comparative analysis was performed to assess both fertilization rates and good-quality embryo rates between couples at different arrest stages undergoing either conventional ICSI or ICSI with assisted oocyte activation (ICSI-AOA). Additionally, whole-exome sequencing (WES, n = 20) was implemented to investigate potential genetic mutations associated with specific fertilization arrest stages. It found that unfertilized oocytes were categorized into four fertilization arrest phenotypes: (i) sperm penetration/fusion deficiency (SPD), (ii) histone incorporation deficiency (HID), (iii) pronuclear-formation deficiency (PFD), and (iv) mixed deficiency. SPD was the primary cause of TFF after IVF (67.8%), and this deficiency was circumvented in ICSI cycles. HID and PFD were the causes of TFF after ICSI. Couples with ≥50.0% oocytes arrested at the histone incorporation stage or ≥75.7% oocytes arrested at the pronuclear formation stage were at high risk of low fertilization rate following ICSI. Couples with ≥50.0% of oocytes arrested at the histone incorporation stage may achieve improved fertilization and embryo outcomes through ICSI-AOA. Genetic mutations associated with male-factor etiologies of fertilization failure have been identified in this patient population. In contrast, for couples with arrest at the PFD, ICSI-AOA shows no beneficial effects on fertilization or embryo development. Genetic mutations associated with female-factor etiologies of fertilization failure have been identified in this patient population. In conclusion, FFA delineates the arrest stages during fertilization failure, facilitates analysis of insemination progression, and provides clinical reference for subsequent treatment cycles.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145763305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Angiotensin II type 1 receptor autoantibody (AT1-AA) is involved in ovulatory disorders: AT1-AA impairs spindle and chromosome organization.","authors":"Yao Chen, Gui-Fang Yang, Yi-Nan Zhang, Xue-Min Li, Ya-Na Yu, De Song, Rui-Xia Guo, Jie Ren, Xiao-Nuo Li, Yu-Hui Shi, Xiao-Li Yang","doi":"10.1093/molehr/gaag003","DOIUrl":"10.1093/molehr/gaag003","url":null,"abstract":"<p><p>Ovulatory disorders are a major cause of infertility. Studies have shown that the renin-angiotensin system (RAS) plays a vital role in the female reproductive system. The angiotensin II type 1 receptor (AT1R), an important mediator of the RAS, may induce anovulation when activated. Previous studies have shown that the levels of AT1R autoantibody (AT1-AA) are significantly higher in the serum of infertile women and are negatively correlated with the oocyte maturation rate. However, systematic understanding of the changes of AT1-AA associated with female ovulatory dysfunction remains limited. In this study, participants were divided into three groups: healthy controls, tubal obstruction group, and ovulatory disorders group. The levels of AT1-AA in serum and follicular fluid were determined using ELISA. The results showed that AT1-AA levels were elevated in both serum and follicular fluid of the ovulatory disorders group compared to the tubal obstruction group. The levels of AT1-AA were negatively correlated with high-quality embryos in the ovulatory disorders group. Follicular fluid AT1-AA levels were an independent risk factor for developing ovulatory disorders. Furthermore, AT1-AA impeded mouse oocyte maturation in vitro, and this effect was suppressed by the second extracellular loop peptide of AT1R. Our findings indicate that follicular fluid AT1-AA is associated with ovulatory disorders and impaired oocyte maturation.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146149753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reduced activin A levels impair urogenital system development and compromise female mouse fertility.","authors":"Eliza Winek, Katarzyna Szczepańska, Marcin Bednarek, Lidia Wolińska-Nizioł, Aneta Suwińska","doi":"10.1093/molehr/gaag007","DOIUrl":"10.1093/molehr/gaag007","url":null,"abstract":"<p><p>Activin A, encoded by the Inhba gene, is a versatile protein crucial for numerous biological processes, and its dysregulation is implicated in various human disorders. However, the perinatal lethality of Inhba knockout mice restricts the delineation of the full extent of this protein's function in the adult organism, particularly in reproduction. Here, we report the identification and characterization of a previously unrecognized InhbaLoxP/LoxP mouse line that exhibits a seven-fold reduction in activin A levels, establishing a novel hypomorphic Inhba model. Unlike the activin A knockout mice, the obtained InhbaLoxP/LoxP individuals survive to adulthood but exhibit impaired growth, as well as defects in hair and eye development. Notably, hypomorphic females display disrupted estrous cycles, elevated luteinizing hormone levels, and severe congenital malformations of the urogenital tract, which markedly compromise their fertility. These abnormalities arise from defective postnatal remodeling of the urogenital sinus, which normally regresses after birth to establish separate vaginal and urethral structures. Persistent urogenital sinus in adult hypomorphic females narrows the vaginal lumen, causes abnormal urethral insertion into the vaginal canal, and likely predisposes to pelvic organ prolapse, collectively preventing successful copulation. This unique mouse model thus uncovers a previously unrecognized, dosage-sensitive requirement for activin A in female reproductive development and anatomy. Overall, our findings highlight Inhba as a critical regulator of urogenital tract remodeling and identify this gene as a potential genetic component in rare human disorders such as persistent urogenital sinus and pelvic organ prolapse, paving the way for investigating the pathogenesis of these conditions.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146132323","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TGFB1/SMAD3-driven macrophage-myofibroblast transition promotes fibrosis progression in endometriosis.","authors":"Yuchan Zhong, Xin Huang, Yujing Li, Ruiying Wang, Xinyu Qiao, Fangyuan Li, Lukanxuan Wu, Chang Liu, Yixian Han, Yunwei Ouyang, Dong Liu, Wei Huang","doi":"10.1093/molehr/gaaf051","DOIUrl":"10.1093/molehr/gaaf051","url":null,"abstract":"<p><p>Endometriosis is a chronic gynecological disorder characterized by progressive fibrosis, which is closely associated with clinical symptoms such as dysmenorrhea and infertility. While myofibroblast activation is central to fibrogenesis, the cellular origins and regulatory mechanisms remain incompletely understood. This study demonstrates that the macrophage-myofibroblast transition (MMT) is a novel source of myofibroblasts in endometriosis and is regulated by the TGFB1/SMAD3 signaling pathway. Using single-cell RNA sequencing, we identified a distinct subpopulation of CD68+ macrophages co-expressing ACTA2 and extracellular matrix (ECM)-related genes in the human endometrium, which exhibited a myofibroblast-like transcriptional profile and were predominantly located at a fibrotic terminal state along the pseudotime trajectory. Histological and ultrastructural analyses revealed varying degrees of fibrosis and elevated TGFB1 expression in eutopic and ectopic endometrium in endometriosis patients and mouse models. Immunofluorescence confirmed that MMT-positive cells, co-expressing CD68 and α-SMA, were enriched in endometriotic tissues and primarily derived from M2 macrophages. In mouse models of endometriosis, pharmacological inhibition of TGFB1/SMAD3 signaling significantly reduced the number of MMT-positive cells and attenuated collagen deposition, particularly in the eutopic endometrium. Furthermore, reduced ectopic lesion volume and epithelial ultrastructural damage following pathway inhibition suggested impaired ectopic lesion survival. These results demonstrate that the TGFB1/SMAD3 pathway-driven MMT might be a novel contributor to endometrial fibrosis in endometriosis. Targeting the TGFB1/SMAD3 signaling axis may provide a dual antifibrotic and anti-lesion strategy, offering therapeutic potential to intervene in the progression of endometriosis.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145244701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ACTRT2 deficiency increases spermatogonia vulnerability to ferroptosis.","authors":"Haicheng Chen, Yanqing Li, Daosheng Luo, Yun Xie, Linyan Lv, Jiahui Yao, Menghui Ma, Xiaoyan Liang, Min Zhang, Xiangzhou Sun, Xuenong Zou, Chunhua Deng, Xing Yang, Guihua Liu","doi":"10.1093/molehr/gaaf041","DOIUrl":"10.1093/molehr/gaaf041","url":null,"abstract":"<p><p>The death of spermatogonia leads to decreased spermatogenesis and male infertility. Spermatogonia are vulnerable to various external damaging factors, which can cause cell death. However, the mechanism is still unclear. In this study, we found that the actin-related protein T2 (ACTRT2) is specifically expressed in testicular tissue and is associated with spermatogenesis. In vitro, when GC-1 cells (spermatogonial cell line) were treated with busulfan, the proportion of cell death in the low-ACTRT2 group increased significantly. Reactive oxygen species accumulation and typical mitochondrial changes associated with ferroptosis occurred. In vivo, the seminiferous tubules in ACTRT2-/- mice were significantly shrunken. In addition, after being treated with busulfan, spermatogenesis in ACTRT2+/- mice decreased significantly compared to that in wild-type mice. In ACTRT2+/- testes, the expression levels of acyl-CoA synthetase long-chain family member 4 and arachidonic acid 15-lipoxygenase-1 (ALOX15) were upregulated, while the expression levels of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) were downregulated. Finally, we found that the expression of solute carrier family 11 member 2 (SLC11A2), iron responsive element binding protein 2 (IREB2), and transferrin receptor protein 1 (TFRC) increased significantly in the low-ACTRT2 group, which transports iron into the cell to increase the intracellular unstable iron pool. In conclusion, ACTRT2 deficiency leads to intracellular iron overload and damage to mitochondria, ultimately increasing spermatogonia vulnerability to ferroptosis.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144855753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A review on macrophage biology and its potential role in spontaneous abortion.","authors":"Xiaoxuan Zhao, Xinyi Ding, Qingnan Fan, Xintong Yao, Linxi Jin, Chaochao Sun, Huanxiao Ke, Qujia Yang, Xiaowei Chen, Saiya Ye, Yuepeng Jiang, Hongli Zhao","doi":"10.1093/molehr/gaaf048","DOIUrl":"10.1093/molehr/gaaf048","url":null,"abstract":"<p><p>Spontaneous abortion (SA) is a challenging and frustrating obstetric complication. Immune dysregulation at the mother-fetal interface has long been recognized as a threat to pregnancy maintenance. Decidual macrophages are key gatekeepers for immune homeostasis at the mother-fetal interface, characterized by their heterogeneity and high plasticity. Abnormalities in their number, function, and phenotype are strongly associated with pregnancy loss. However, the specific regulation mechanisms remain elusive. Here, we outline the origin and identity of the endometrial macrophages and review their diverse changes in phenotypes and functions to pregnancy initiation. More importantly, we highlight the underlying mechanisms mediating aberrant changes in macrophage polarization and functions in the context of SA, involving epigenetic landscape dysregulation, metabolic reprogramming, and aberrant communication between macrophages and other component cells at the maternal-fetal interface. Altogether, these provide a clear framework for understanding the crucial roles and prospective therapeutic targets of macrophages in SA.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145244661","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An Nlrp5-null mutation leads to attenuated de novo methylation in oocytes, accompanied by a significant reduction in DNMT3L.","authors":"Leah Nic Aodha, Alexandra Pokhilko, Leah U Rosen, Styliani Galatidou, Edyta Walewska, Christian Belton, Antonio Galvao, Hanneke Okkenhaug, Lu Yu, Asif Nakhuda, Bill Mansfield, Soumen Khan, David Oxley, Montserrat Barragán, Gavin Kelsey","doi":"10.1093/molehr/gaaf055","DOIUrl":"10.1093/molehr/gaaf055","url":null,"abstract":"<p><p>Nlrp5 encodes a core component of the subcortical maternal complex (SCMC), a cytoplasmic protein structure unique to the mammalian oocyte and cleavage-stage embryo. NLRP5 mutations have been identified in patients presenting with early embryo arrest, recurrent molar pregnancies, and imprinting disorders. Correct patterning of DNA methylation over imprinted domains during oogenesis is necessary for faithful imprinting of genes. It was previously shown that oocytes with mutation in the human SCMC gene KHDC3L had globally impaired methylation, indicating that integrity of the SCMC is essential for correct establishment of DNA methylation at imprinted regions. Here, we present a multi-omic analysis of an Nlrp5-null mouse model, which in germinal vesicle (GV)-stage oocytes displays a misregulation of a broad range of maternal proteins, including proteins involved in several key developmental processes. This misregulation likely underlies impaired oocyte developmental competence. Amongst impacted proteins are several epigenetic modifiers, including a substantial reduction in DNMT3L; we show that de novo DNA methylation is attenuated in Nlrp5-null oocytes, including at some imprinting control regions. This provides evidence for a mechanism of epigenetic impairment in oocytes, which could contribute to downstream misregulation of imprinted genes.</p>","PeriodicalId":18759,"journal":{"name":"Molecular human reproduction","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12704423/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145549936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}