Epigenetics最新文献

{"title":"The technology landscape for detection of DNA methylation in cancer liquid biopsies.","authors":"Isabelle Neefs, Joe Ibrahim, Marc Peeters, Guy Van Camp, Ken Op de Beeck","doi":"10.1080/15592294.2025.2453273","DOIUrl":"10.1080/15592294.2025.2453273","url":null,"abstract":"<p><p>DNA methylation is a well-studied epigenetic factor and has become a powerful player in the cancer biomarker research field. Together with the rising interest in methylation biomarkers, the technological advances for the detection of DNA methylation have been immense. This has led to a plethora of different methods. The first methods were established for DNA methylation detection in genomic DNA, while new methods have focused more on compatibility with the emerging interest of cell-free DNA (cfDNA) from liquid biopsies. As DNA methylation detection in cfDNA brings its own challenges, a shift from the gold standard bisulfite conversion towards enzymatic conversion methods can be observed in recent years. In this review, we aim to summarize the classic and more recent DNA methylation detection methods for liquid biopsies. Importantly, the few existing European Certified In Vitro Diagnostics (CE-IVD) clinical applications for liquid biopsies are also described, underlining the potential of DNA methylation as a detection biomarker in cfDNA. Furthermore, we provide some insights into how the field might evolve in the future, where we believe enzymatic conversion might become a new gold standard and direct sequencing methods, such as ONT-sequencing, will get an important place in the epigenetic research field. Lastly, we believe that multi-omics technologies, which can combine diverse types of biomarkers, will most likely become more important in future clinical applications. Moreover, novel recent technologies are being developed and show promising clinical applications. Taken together, methylation biomarkers are becoming more important for clinical implementation.</p>","PeriodicalId":11767,"journal":{"name":"Epigenetics","volume":"20 1","pages":"2453273"},"PeriodicalIF":3.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11792835/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145713694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SIRT1/DNMT3B-mediated epigenetic gene silencing in response to phytoestrogens in mammary epithelial cells.","authors":"Yuexi Ma, Cayla Boycott, Jiaxi Zhang, Rekha Gomilar, Tony Yang, Barbara Stefanska","doi":"10.1080/15592294.2025.2473770","DOIUrl":"10.1080/15592294.2025.2473770","url":null,"abstract":"<p><p>We performed an integrated analysis of genome-wide DNA methylation and expression datasets in normal cells and healthy animals exposed to polyphenols with estrogenic activity (i.e. phytoestrogens). We identified that phytoestrogens target genes linked to disrupted cellular homeostasis, e.g. genes limiting DNA break repair (<i>RNF169</i>) or promoting ribosomal biogenesis (<i>rDNA</i>). Existing evidence suggests that DNA methylation may be governed by sirtuin 1 (SIRT1) deacetylase via interactions with DNA methylating enzymes, specifically DNMT3B. Since SIRT1 was reported to be regulated by phytoestrogens, we test whether phytoestrogens suppress genes related to disrupted homeostasis via SIRT1/DNMT3B-mediated transcriptional silencing. Human MCF10A mammary epithelial cells were treated with phytoestrogens, pterostilbene (PTS) or genistein (GEN), followed by analysis of cell growth, DNA methylation, gene expression, and SIRT1/DNMT3B binding. SIRT1 occupancy at the selected phytoestrogen-target genes, <i>RNF169</i> and <i>rDNA</i>, was accompanied by consistent promoter hypermethylation and gene downregulation in response to GEN, but not PTS. GEN-mediated hypermethylation and SIRT1 binding were linked to a robust DNMT3B enrichment at <i>RNF169</i> and <i>rDNA</i> promoters. This was not observed in cells exposed to PTS, suggesting a distinct mechanism of action. Although both SIRT1 and DNMT3B bind to <i>RNF169</i> and <i>rDNA</i> promoters upon GEN, the two proteins do not co-occupy the regions. Depletion of SIRT1 abolishes GEN-mediated decrease in <i>rDNA</i> expression, suggesting SIRT1-dependent epigenetic suppression of <i>rDNA</i> by GEN. These findings enhance our understanding of the role of SIRT1-DNMT3B interplay in epigenetic mechanisms mediating the impact of phytoestrogens on cell biology and cellular homeostasis.</p>","PeriodicalId":11767,"journal":{"name":"Epigenetics","volume":"20 1","pages":"2473770"},"PeriodicalIF":3.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881848/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143540624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Methylation profile of individuals with sickle cell trait.","authors":"Ana Gabriela Vasconcelos, Mari Johnson, Yanwei Cai, Li Hsu, Nora Franceschini, Paul L Auer, Charles Kooperberg, Laura M Raffield, Alex P Reiner","doi":"10.1080/15592294.2025.2539234","DOIUrl":"10.1080/15592294.2025.2539234","url":null,"abstract":"<p><p>Sickle cell trait (SCT) is due to heterozygosity for the β-globin sickle cell mutation. SCT recently has been associated with increased risk of various adverse health outcomes. DNA methylation (DNAm) is one potential mechanism by which SCT may impact disease risk. To identify DNAm sites associated with SCT, we conducted an epigenome-wide association (EWAS) meta-analysis using whole blood Illumina EPIC array data available in a total of 3,677 African American participants (including 1,071 with SCT) from the Women's Health Initiative and Jackson Heart Study. We identified 103 differentially methylated CpGs and 119 differentially methylated regions associated with SCT. The strongest signals were hypermethylated cis loci within predicted regulatory elements within or near the β-globin gene cluster on chromosome 11. Beyond the globin locus, SCT-associated DMPs were enriched in genes involved in redox regulation and oxidative stress. We also demonstrate an association of SCT with differences in biological age and epigenetic age acceleration, though the pattern and strength of association differ according to the epigenetic clock used. Specifically, more recent epigenetic clocks that incorporate clinical phenotypes or laboratory biomarkers related to adverse health outcomes are associated with accelerated aging among individuals with SCT compared to African American controls. Our results lay the groundwork for future study of the role of DNAm in biologic aging and related health outcomes among individuals with SCT.</p>","PeriodicalId":11767,"journal":{"name":"Epigenetics","volume":"20 1","pages":"2539234"},"PeriodicalIF":3.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12323419/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144783770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Placental malaria induces a unique methylation profile associated with fetal growth restriction.","authors":"Nida Ozarslan, Corina Mong, John Ategeka, Lin Li, Sirirak Buarpung, Joshua F Robinson, Jimmy Kizza, Abel Kakuru, Moses R Kamya, Grant Dorsey, Philip J Rosenthal, Stephanie L Gaw","doi":"10.1080/15592294.2025.2475276","DOIUrl":"10.1080/15592294.2025.2475276","url":null,"abstract":"<p><p>Fetal growth restriction (FGR) is associated with perinatal death and adverse birth outcomes, as well as long-term complications, including increased childhood morbidity, abnormal neurodevelopment, and cardio-metabolic diseases in adulthood. Placental epigenetic reprogramming associated with FGR may mediate these long-term outcomes. Placental malaria (PM), characterized by sequestration of <i>Plasmodium falciparum</i>-infected erythrocytes in placental intervillous space, is the leading global cause of FGR, but its impact on placental epigenetics is unknown. We hypothesized that placental methylomic profiling would reveal common and distinct mechanistic pathways of non-malarial and PM-associated FGR. We analyzed placentas from a US cohort with no malaria exposure (<i>n</i> = 12) and a cohort from eastern Uganda, a region with a high prevalence of malaria (<i>n</i> = 12). From each site, 8 cases of FGR and 4 healthy controls were analyzed. PM was diagnosed by placental histopathology. We compared the methylation levels of over 850K CpGs of the placentas using Infinium MethylationEPIC v1 microarray. Non-malarial FGR was associated with 65 differentially methylated CpGs (DMCs), whereas PM-FGR was associated with 133 DMCs, compared to their corresponding controls without FGR. One DMC (cg16389901, located in the promoter region of <i>BMP4</i>) was commonly hypomethylated in both groups. We identified 522 DMCs between non-malarial FGR vs. PM-FGR placentas, independent of differing geographic location or cellular composition. Placentas with PM-associated FGR have distinct methylation profiles compared to placentas with non-malarial FGR, suggesting novel epigenetic reprogramming in response to malaria. Larger cohort studies are needed to determine the distinct long-term health outcomes in PM-associated FGR pregnancies.</p>","PeriodicalId":11767,"journal":{"name":"Epigenetics","volume":"20 1","pages":"2475276"},"PeriodicalIF":2.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11901535/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143572486","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic signatures of maternal-fetal health: insights from cord blood and placenta.","authors":"Jagadeesh Puvvula, Joseph M Braun, Emily A DeFranco, Shuk-Mei Ho, Yuet-Kin Leung, Shouxiong Huang, Xiang Zhang, Ann M Vuong, Stephani S Kim, Zana Percy, Aimin Chen","doi":"10.1080/15592294.2025.2508067","DOIUrl":"10.1080/15592294.2025.2508067","url":null,"abstract":"<p><p>The placenta is vital for fetal growth, and its methylation patterns reflect placental function, affecting the fetus and providing insights into disease origins. While cord blood methylation is convenient for assessing the fetal environment, methylation profiles vary by tissue due to variance in cell populations, function, and life stage. As tissue differences extensively contribute to the DNA methylation patterns, using surrogate samples such as cord blood may result in inconsistent findings. In this study, we aim to quantify the correlation of <i>cytosine-phosphate-guanine dinucleotides (CpGs) between paired cord blood and placenta</i> samples. Using the Infinium Human Methylation 450 K BeadChip, we compared methylation patterns in cord blood mononuclear cells (CBMC; <i>n</i> = 54), the maternally-facing side of placental tissue (MP; <i>n</i> = 68), and the fetal-facing side of placental tissue (FP; <i>n</i> = 67). Methylation patterns from the FP (6,021 CpGs) were significantly correlated with CBMC compared to the MP (2,862 CpGs). These CpGs were related to the biological (mitotic cell) process and molecular function (ribonucleoprotein complex binding). Our findings quantified CpG site correlation between cord blood and placenta, providing a valuable reference for future studies on placental health that rely on cord blood methylation in the absence of placental biospecimens.</p>","PeriodicalId":11767,"journal":{"name":"Epigenetics","volume":"20 1","pages":"2508067"},"PeriodicalIF":2.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12118431/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144127031","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex-stratified piRNA expression analysis reveals shared functional impacts of perinatal lead (Pb) exposure in murine hearts.","authors":"Kimberley E Sala-Hamrick, Kai Wang, Bambarendage P U Perera, Maureen A Sartor, Laurie K Svoboda, Dana C Dolinoy","doi":"10.1080/15592294.2025.2542879","DOIUrl":"10.1080/15592294.2025.2542879","url":null,"abstract":"<p><p>The landscape of PIWI-interacting RNA (piRNA) expression in the heart is poorly understood, particularly regarding sex differences. Altered piRNA expression has been reported in cardiovascular disease (CVD), and although exposure to the metal lead (Pb) is strongly associated with CVD risk, no studies have investigated Pb's effects on cardiac piRNAs. This study aimed to characterize piRNA expression in the murine heart and assess sex-specific effects of human-relevant maternal Pb exposure on adult offspring cardiac piRNA expression. piRNAs were identified from whole mouse hearts using sodium periodate exclusion of small RNA and subsequent sequencing. Control mice expressed 18,956 piRNAs in combined-sex analysis; sex-specific analyses revealed 9,231 piRNAs in female hearts and 5,972 piRNAs in male hearts. Genomic mapping showed 28-41% aligned to introns, while 12-28% mapped to exons. Comparing control and Pb-exposed hearts, we found more potential Pb-induced expression changes in females (847) compared to males (187) (p-value < 0.05 and |logFC| > 1). These piRNAs were significantly enriched near genes involved in biological processes related to heart function and CVD development, including mitochondrial function, energy metabolism, and cardiac muscle structure (FDR < 0.05). Overall, we characterized combined and sex-stratified piRNA expression in both control and Pb-exposed murine hearts. In addition to providing a foundation for sex-specific piRNA expression in the heart, these findings suggest a novel epigenetic mechanism by which developmental Pb exposure may impact CVD risk later in life. Future studies will link these sex-specific molecular changes to Pb-induced alterations in cardiac function.</p>","PeriodicalId":11767,"journal":{"name":"Epigenetics","volume":"20 1","pages":"2542879"},"PeriodicalIF":3.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12341058/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144816099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insights into WDR5: unveiling its functions, regulation, and impact on skeletal muscle.","authors":"Erick Bahena-Culhuac, Mauricio Hernández-Somilleda, José Manuel Hernández-Hernández","doi":"10.1080/15592294.2025.2573998","DOIUrl":"10.1080/15592294.2025.2573998","url":null,"abstract":"<p><p>WD40-repeat-containing protein 5 (WDR5) is a highly conserved multifunctional scaffold protein with a toroidal structure, facilitating interactions with numerous partners through its WDR5-binding motif (WBM) and WDR5-interacting (WIN) sites. It plays a critical role in histone modifications, including H3K4 methylation (H3K4me), histone acetylation, and deacetylation, influencing stem cell maintenance and differentiation. Recent studies highlight its involvement in muscle homeostasis, particularly in skeletal muscle progenitor cells, where it regulates PAX7-driven myogenic factor expression. Additionally, WDR5 governs epigenetic programs in smooth muscle by modulating H3K4me marks on lineage-specific genes. Despite extensive research on its role in cancer and chromatin remodeling, its broader physiological functions remain underexplored. This review examines WDR5's regulatory mechanisms, including its modulation by long non-coding RNAs (lncRNAs), post-translational modifications (PTMs), and microproteins, while emphasizing its relevance to muscle biology. Understanding WDR5's interactome and regulatory networks could provide novel insights into muscle regeneration, stem cell dynamics, and potential therapeutic strategies for muscular disorders and regenerative medicine.</p>","PeriodicalId":11767,"journal":{"name":"Epigenetics","volume":"20 1","pages":"2573998"},"PeriodicalIF":3.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12530494/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145285916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of blood-derived DNA methylation biomarkers of glaucoma and intraocular pressure measurements in three European ancestry cohorts including the Canadian longitudinal study on aging.","authors":"Xiaofan Jiang, Omar A Mahroo, Anthony P Khawaja, Dorota Skowronska-Krawczyk, David A Mackey, Janey L Wiggs, Christopher J Hammond, Pirro G Hysi, Christopher G Bell","doi":"10.1080/15592294.2025.2566496","DOIUrl":"10.1080/15592294.2025.2566496","url":null,"abstract":"<p><p>Glaucoma is a major cause of blindness globally and its prevalence rises with age. This study explored systemic blood-derived DNA methylation epigenetic biomarkers for association with glaucoma and intraocular pressure (IOP). Blood-derived DNA methylation (DNAm) was analyzed in 1,201 European participants from the Canadian Longitudinal Study on Aging (CLSA; Illumina EPIC v1 array) and 843 European participants from TwinsUK (450k array). An Epigenome-Wide Association Study (EWAS) for glaucoma and IOP was conducted, adjusting for age, sex, tobacco smoking, and leukocyte cell types. DNAm-based EpiScores estimates for 108 plasma protein levels were evaluated for associations with glaucoma and IOP. Additionally, 'biological' age acceleration, estimated using five established DNAm 'clocks,' was assessed for glaucoma and IOP and replicated in The Health and Retirement Study (HRS; <i>n</i> = 3,453). EWAS analyses of glaucoma and IOP in individual cohorts did not identify genome-wide significant associations. However, a combined EWAS for overlapping probes in both cohorts identified two epigenome-wide significant CpGs: cg03498697 in the <i>FRMD3</i> promoter (<i>p</i> = 6.86x10^-8) and cg06044751 intronically within <i>PALLD</i> (<i>p</i> = 1.76x10^-7). EpiScore analysis revealed one IOP Bonferroni-significant association with TNFRSF1B levels in the meta-analysis of both cohorts (<i>p</i> = 1.31x10^-4). DNAm 'clock' analysis in the HRS identified a GrimAge-positive age acceleration associated with glaucoma (<i>p</i> = 0.01). This study identified significant epigenetic blood-derived biomarkers that are associated with glaucoma and IOP. These findings warrant replication in larger and more diverse populations as well as via longitudinal analysis to assess their robustness and potential predictive power.</p>","PeriodicalId":11767,"journal":{"name":"Epigenetics","volume":"20 1","pages":"2566496"},"PeriodicalIF":3.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12536625/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145312647","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DNA methylation markers of insulin resistance surrogate measures in the Atherosclerosis Risk in Communities (ARIC) study.","authors":"Jeewoen Shin, Jan Bressler, Megan L Grove, Michael Brown, Elizabeth Selvin, James S Pankow, Myriam Fornage, Alanna C Morrison, Chloé Sarnowski","doi":"10.1080/15592294.2025.2498857","DOIUrl":"https://doi.org/10.1080/15592294.2025.2498857","url":null,"abstract":"<p><p>Insulin resistance (IR) is a risk factor for cardiovascular diseases and type 2 diabetes. Associations between DNA methylation (DNAm) and IR have been less studied in African ancestry (AA) populations than those of European ancestry (EA). We aimed to identify associations between whole blood DNAm and IR in up to 1,811 AA and 964 EA participants from the Atherosclerosis Risk in Communities (ARIC) study. We quantified IR using three surrogate measures: the homeostasis model assessment of insulin resistance (HOMA-IR), the triglyceride-glucose index (TyG), and the triglyceride glucose-body mass index (TyG-BMI). We used ancestry-stratified linear regression models to conduct epigenome-wide association studies of IR, adjusting for batch effects and relevant covariates. Among 484,436 tested CpG sites, 39 were significantly associated with IR, of which 31% (10 in AA and two in EA) were associated with TyG-BMI and not previously reported for IR or related traits. These include a positive association at cg18335991-<i>SEMA7A</i> in AA. <i>SEMA7A</i> inhibits adipogenesis of preadipocytes and lipogenesis of mature adipocytes. DNAm levels at cg18335991 have been reported to be negatively associated with <i>SEMA7A</i> expression in blood. After additionally adjusting for smoking and drinking status, 15 of the 39 significant CpG sites remained significant or suggestive. Our study identified novel IR-associated CpG sites, contributing to a broader understanding of the epigenetic mechanisms underlying IR in diverse populations.</p>","PeriodicalId":11767,"journal":{"name":"Epigenetics","volume":"20 1","pages":"2498857"},"PeriodicalIF":2.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12064056/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143970825","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Higher sperm H3K4me3 levels are associated with idiopathic recurrent pregnancy loss.","authors":"Delna Irani, Deepshikha Arya, Deepti Tandon, Vandana Bansal, Anushree Patil, Dipty Singh","doi":"10.1080/15592294.2025.2498859","DOIUrl":"https://doi.org/10.1080/15592294.2025.2498859","url":null,"abstract":"<p><p>During fertilization, spermatozoa contribute genetic and epigenetic factors such as chromatin packaged with protamines and histones; DNA methylome, non-coding RNAs, etc. Human sperm chromatin retains 5-15% nucleosomes which can play a key role in embryonic development. Recurrent pregnancy loss (RPL) is a condition mainly attributed to defects in embryo and placenta development. Majority of the known RPL factors are of maternal contribution, while  ~50% RPL cases are termed idiopathic (iRPL). In addition to paternal genetic factors, epigenetic factors via sperm could also be responsible for iRPL. Hence, we investigated alterations in retained nucleosome content of iRPL sperm (<i>n</i> = 46) as compared to fertile male population (<i>n</i> = 40). We measured the relative abundance of core histone H4 and Protamine-2 content along with the modified histones H4Ac, H3K4me3, H3K27me3 and H3K9me3 by flow cytometry. H4 and Protamine-2 levels were comparable in both groups and showed significant negative correlation. The iRPL group had significantly higher levels of sperm H3K4me3 as compared to the fertile control group. The other modified histones and protamine levels showed no significant alterations. Furthermore, sperm DFI was found to be significantly positively correlated with H4 levels in both groups. No significant correlation was observed between sperm 5-mC levels with H4 and other modified histone levels. A fraction of H3K4me3 enrichment is now known to resist embryonic epigenetic reprogramming; and hence, such elevated levels in the sperm would question its developmental competence leading to RPL pathology. Also, incidence of sperm DNA fragmentation is associated with increased histone retention in both fertile and iRPL cases.</p>","PeriodicalId":11767,"journal":{"name":"Epigenetics","volume":"20 1","pages":"2498859"},"PeriodicalIF":2.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12054925/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143984748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}