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PubMed2026

Target Antigen Identification for Antibody Drug Conjugate Therapy in Biliary Tract Cancer.

BACKGROUND: Data on antibody-drug conjugates (ADCs) target expression prevalence, intertumoral heterogeneity, genomic concordance, and its effect on clinical outcomes is limited in biliary tract cancers (BTC). METHODS: Resected primary BTC specimens, and when available, matched metastatic samples were assembled into tissue microarrays and tested for CLDN18.2, c-MET, Nectin-4, TROP2, and HER2 expression by immunohistochemistry (IHC). A subset underwent targeted next-generation sequencing using MSK-IMPACT (NCT01775072). Exploratory associations of target expression with clinicopathologic parameters, genomic alterations, recurrence-free (RFS), and overall (OS) survival were evaluated. RESULTS: 65 patients with resected BTC and 18 paired metastatic sites were identified-43% extrahepatic cholangiocarcinoma, 40% intrahepatic cholangiocarcinoma, and 17% gallbladder cancer. All evaluated target antigens were expressed; percent positivity and H-score ≥200 were: TROP2 (83%, 26%), c-MET (75%, 26%), Nectin-4 (66%, 35%), and CLDN18.2 (46%, 7.7%). HER2 overexpression occurred in 3.1% of tumors. Overall agreement among paired primary and metastatic samples on calling either positive or negative ranged from 43% to 75% with the highest observed for HER2 [75%; κ=0.29 (95%CI: -0.32 to 0.91)] and TROP2 (71%; κ not available) and lowest for c-MET, CLDN18.2, and Nectin-4. Frequently altered genes included TP53 (36%), SMAD4 (27%), ELF3 (21%). We observed no significant association between target antigen expression with genomics, RFS, or OS. CONCLUSIONS: BTC displays frequent but heterogeneous expression of multiple ADC targets. These hypothesis generating findings suggest inherent complexity of target protein quantification, target threshold determination, and target sampling discordance. Future studies will be required to refine our understanding the utlitiy of ADCs in BTC.

Journal Article↗
PubMed2026

Establishment of a multi-targeted magnetic combined enrichment system for circulating tumor cells in gastric cancer and analysis of their genomic profiles.

Background: This study aims to establish an efficient Circulating tumor cells (CTCs) multi-targeted magnetic combined sorting system for Gastric cancer (GC), while comparing it with tissue and circulating tumor DNA (ctDNA) samples to evaluate its feasibility and consistency for genomic profiling analysis. Method: Establish an efficient CTCs sorting system for GC targeting epithelial cell adhesion molecule, cell surface vimentin, and protein tyrosine kinase 7, and evaluate its physicochemical properties and cell capture efficiency. Assess the feasibility of tumor cell detection through animal experiments. Sixty-eight GC patients underwent CTCs detection. Clinical information was analyzed to evaluate the clinical utility of CTCs in the auxiliary diagnosis of GC. Next-generation sequencing was performed on GC tissue, CTCs, and ctDNA samples to assess the consistency of genetic mutations across different sample types. Results: The constructed CTCs sorting system exhibits excellent physicochemical properties, achieving a capture rate of 94.68%. Animal studies confirm a positive correlation between tumor cells count and tumor volume. The number of CTCs in the blood of GC patients is significantly correlated with tumor size, stage, and metastasis. The CTCs count in GC patients is significantly higher than in healthy individuals and high-risk groups for cancer, with diagnostic sensitivity and specificity of 97.29% and 97.73%, respectively. The mutation detection rate in CTCs samples was significantly higher than that in tissue and ctDNA samples. The concordance rate between CTCs and tissue mutations was 24.32%, while the concordance rate between CTCs and ctDNA mutations was 19.05%. Conclusion: This study successfully established a multi-target combined CTCs multi-targeted magnetic combined sorting system for GC. CTCs detection based on this system can be used for the auxiliary diagnosis of GC patients. Furthermore, compared to GC tissue and ctDNA samples, CTCs detection enables more comprehensive genomic profiling analysis and serves as an important supplement to GC genomic analysis.

Humans↗
PubMed2026

Circulating Tumor DNA in Breast Cancer: A Liquid Biopsy Revolution for Non-Invasive Genomic Profiling and Clinical Decision-Making.

Breast cancer remains the most frequently diagnosed cancer and a leading cause of cancer-related mortality among women worldwide, underscoring the need for accurate, minimally invasive biomarkers to support precision oncology. Conventional tissue biopsy remains the standard for molecular characterization but is limited by its invasiveness, inability to capture spatial and temporal tumor heterogeneity, and challenges in serial monitoring. Circulating tumor DNA (ctDNA), a tumor-derived fraction of cell-free DNA, has emerged as a promising liquid biopsy biomarker capable of providing real-time genomic information throughout disease progression. This narrative review examines recent advances in ctDNA biology, analytical technologies, clinical applications, current limitations, and future directions in breast cancer management. A structured literature search of PubMed/MEDLINE, Scopus, Embase, Web of Science, and Google Scholar identified relevant English-language publications from 2015 to 2026. Current evidence indicates that highly sensitive platforms, including digital PCR, BEAMing, and next-generation sequencing, can detect clinically actionable alterations in genes such as PIK3CA, ESR1, TP53, ERBB2, AKT1, and BRCA1/2. ctDNA has demonstrated particular utility in identifying minimal residual disease, monitoring therapeutic response, detecting emerging resistance mechanisms, and guiding targeted treatment selection in advanced breast cancer. However, applications in early cancer detection, population screening, and artificial intelligence-assisted clinical decision-making remain investigational. Widespread clinical implementation is constrained by low ctDNA abundance in early-stage disease, analytical variability, limited assay standardization, and cost considerations. Continued technological innovation, prospective multicenter validation, standardized testing protocols, and evidence-based clinical guidelines are essential to fully integrate ctDNA into routine precision breast cancer care.

breast cancer↗
PubMed2026

Co-Occurring EGFR L858R Mutation and HER2 Amplification in NSCLC Identified by Stepwise Molecular Profiling.

BACKGROUND The coexistence of multiple oncogenic drivers in non-small cell lung cancer (NSCLC) is a rare and diagnostically challenging molecular configuration. Conventional polymerase chain reaction (PCR)-based testing may fail to detect co-occurring genomic alterations, potentially limiting therapeutic options, particularly in resource-constrained settings. CASE REPORT We describe the case of a 54-year-old non-smoking woman diagnosed with Stage IIIA lung adenocarcinoma in 2020. Initial PCR-based molecular testing was negative for EGFR mutations. Following disease progression with brain metastases and severe chemotherapy toxicity, stepwise molecular profiling in a resource-limited setting identified HER2 (ERBB2) amplification via fluorescence in situ hybridization (FISH). The patient achieved 23 months of clinical and radiological stabilization on trastuzumab. Subsequent next-generation sequencing (NGS) analysis of archived tissue revealed a previously undetected estimated glomular filtration rate (EGFR) L858R mutation. In late April 2025, new lesions appeared in the lungs, indicating disease progression. Based on the previously verified EGFR L858R mutation, the treatment strategy was revised and gefitinib was initiated in May 2025. CONCLUSIONS This case illustrates that co-occurring EGFR and HER2 alterations can remain undetected following initial limited molecular testing, and that stepwise molecular profiling in a resource-constrained setting can facilitate identification of therapeutically actionable targets. The sequential clinical responses observed are consistent with the biological relevance of both alterations, although broader conclusions regarding diagnostic strategy or driver hierarchy cannot be drawn from a single observation.

Humans↗
PubMed2026

[Genetic and functional characterization of a novel KIT splicing variant in a Chinese three-generation pedigree with piebaldism].

OBJECTIVES: To investigate the genetic etiology of a three-generation pedigree affected with piebaldism. METHODS: Next-generation sequencing and Sanger sequencing were employed to detect and verify gene variants. Bioinformatics tools were used to predict the effects of candidate variants on splicing and protein function. RT-PCR and Sanger sequencing were further performed to validate the impact of the variant on RNA splicing, and homology modeling was applied to predict its effect on the three-dimensional structure of the KIT protein. The pathogenicity of the variant was then classified according to the guidelines of the American College of Medical Genetics and Genomics (ACMG) and the UK Association for Clinical Genomic Science (ACGS). RESULTS: A heterozygous insertion variant near the splice site, c.1990+8_1990+9insTGCACCATTGGAGGTAAA, was identified in the KIT gene in the proband and was found to co-segregate with the phenotype within the family. RT-PCR and cDNA sequencing revealed that this variant led to aberrant splicing during transcription, resulting in a 21 bp in-frame insertion in the mRNA, which encodes an extra 7 amino acids within the tyrosine kinase domain and may thus affect protein function. In silico predictions, together with the experimental findings, supported classification of this variant as likely pathogenic according to relevant variant interpretation guidelines. CONCLUSIONS: The heterozygous splice-site insertion variant KIT:c.1990+8_1990+9insTGCACCATTGGAGGTAAA is the genetic cause of piebaldism in this pedigree.

Genetics diagnosis↗
PubMed2026

Gastric amphicrine carcinoma in the stomach: an unexpected presentation of MUTYH-associated polyposis.

Amphicrine carcinomas of the stomach, defined by dual exocrine and neuroendocrine differentiation within the same neoplastic cell, are exceedingly rare. MUTYH-associated polyposis (MAP) is an autosomal recessive polyposis syndrome characterized by multiple colorectal adenomas and variable upper gastrointestinal involvement; however, amphicrine carcinomas have not been previously documented in this setting. We report a gastric amphicrine carcinoma arising in the background of extensive fundic gland polyposis in a patient with MAP. Endoscopy revealed a 3.5-cm flat elevated lesion in the gastric fundus amid extensive fundic gland polyposis. Histologically, the tumor consisted of a single population of cells exhibiting combined glandular and neuroendocrine differentiation without zonal or biphasic architecture, and many of these cells demonstrated true amphicrine morphology. Immunohistochemistry confirmed co-expression of cytokeratin and the neuroendocrine markers chromogranin A and synaptophysin in the same cell population. Germline targeted next-generation sequencing identified biallelic MUTYH variants in trans (c.733C>T, p.Arg245Cys [likely pathogenic]; c.842C>T, p.Ala281Val [variant of uncertain significance]), supporting a diagnosis of MAP. To our knowledge, this is the first reported case of a gastric amphicrine carcinoma in a MAP patient, expanding the spectrum of MAP-associated upper gastrointestinal neoplasia and underscoring the importance of vigilant endoscopic surveillance in hereditary polyposis syndromes.

Carcinoma↗
PubMed2026

Mitochondrial DNA diversity in Ecuadorian populations: Recurrence of variant 16136 within haplogroup B2.

The identification of lineage-defining variants, frequently found in the coding region of mitochondrial DNA (mtDNA), is essential for refining haplogroup classification. Most mtDNA studies in South American populations have focused on the control region (CR), which has provided important insights into population structure and maternal lineage origins, although information needed for more robust phylogenetic resolution has been neglected. This study investigates the maternal genetic structure of Ecuadorian populations by combining CR and whole mitogenome analyses. Sequences from the mtDNA CR were obtained from 461 individuals (253 Mestizos and 208 Native Americans), while complete mitogenomes were sequenced for 127 individuals to improve phylogenetic resolution by identifying lineage-defining variants present in coding region. Most mtDNA haplogroups in the two population groups analyzed were of Native American origin (A2, B2, B4, C1, D1, D4), with significant differences in the distribution of specific lineages between them. Among Mestizos, African haplogroups (all within the L branches) and Eurasian haplogroups (H, K, R, U) were detected at low frequencies, whereas no African lineages were observed among Native Americans. The results obtained highlighted a heterogeneity within Ecuadorian populations that must be considered when developing mtDNA haplotype databases for forensic purposes. Whole mitogenome sequences enabled the identification of variants that refined haplogroup classifications, provided a more accurate reconstruction of the maternal genetic diversity, and improve the discrimination between Native American and Asian maternal lineages within haplogroup B4b.

Humans↗
PubMed2026

Gastrointestinal involvement in Ehlers-Danlos syndrome classical-like type 2 associated with a novel AEBP1 splice-site variant.

Ehlers-Danlos syndrome classical-like type 2 (clEDS2) is a rare autosomal recessive connective tissue disorder caused by biallelic loss-of-function variants in the gene encoding adipocyte enhancer-binding protein 1 (AEBP1). While cutaneous and skeletal manifestations are commonly observed, gastrointestinal complications, including bowel rupture, have been reported only rarely, and their histopathological basis remains poorly characterized. Here, we report findings of molecular investigations, gastrointestinal histopathological evaluation, and long-term clinical follow-up in the 16th reported patient with AEBP1-related clEDS2, complicated by spontaneous bowel perforation. A homozygous AEBP1 splice-site variant (NM_001129.5:c.1401-2 A > G) was identified by a custom next-generation sequencing-based panel analysis for hereditary connective tissue disorders. Transcript-level analysis by reverse transcription-polymerase chain reaction and Sanger sequencing demonstrated complete skipping of exon 12, resulting in a frameshift and predicted loss of function. Clinically, the patient experienced postoperative perforation in the sigmoid colon shortly after rectal cancer surgery, followed nearly 20 years later by spontaneous small intestinal perforation. Histopathological examination of the affected colonic tissue demonstrated mildly widened intermuscular spaces without other overt structural abnormalities. Notably, repeated upper and lower gastrointestinal endoscopic procedures were performed during long-term oncological surveillance without procedure-related bowel perforation. This observation could offer an opportunity to learn about gastrointestinal involvement in AEBP1-related clEDS2 and suggests that its gastrointestinal manifestations may differ in clinical context from those typically associated with vascular Ehlers-Danlos syndrome, warranting further investigation as additional cases are accumulated.

Humans↗
PubMed2026

Emerging Strategies Targeting the PI3K/AKT/mTOR Pathway in HR+/HER2- Advanced Breast Cancer.

Hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer accounts for approximately 70% of breast cancer cases. Despite recent advances with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), resistance inevitably develops, often driven by activation of the phosphatidylinositol 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) pathway. Genetic alterations such as PIK3CA mutations (present in ~ 45% of HR+/HER2- tumors), AKT1 mutations, and PTEN loss contribute to endocrine resistance and poor outcomes. This review summarizes emerging strategies targeting this pathway to overcome resistance in advanced disease. Isoform-specific PI3K inhibitors, including alpelisib and inavolisib, have demonstrated clinically meaningful progression-free survival benefits in PIK3CA-mutated populations, with inavolisib showing improved tolerability and efficacy. In contrast, pan-PI3K inhibitors such as buparlisib have been constrained by toxicity. Targeting downstream signaling, AKT inhibitors have also shown benefit: capivasertib has demonstrated clinical efficacy leading to US Food and Drug Administration approval, while ipatasertib has yielded encouraging results, particularly in tumors harboring PIK3CA, AKT1, or PTEN alterations. Mammalian target of rapamycin inhibitors, notably everolimus, have shown efficacy irrespective of mutation status. The dual PI3K-mTOR inhibitor (gedatolisib) has also shown promising progression-free survival benefit in a PIK3CA wild-type population. Next-generation agents, including mutant-selective PI3Kα inhibitors and bi-steric mTOR complex 1 inhibitors, are under active investigation. Optimal sequencing of these agents alongside endocrine therapy and CDK4/6i options remain a critical question, as does integration of genomic testing to guide therapy. Future directions include rational combination strategies, improved biomarker-driven selection, and novel modalities such as proteolysis-targeting chimeras (PROTACs). Collectively, these advances aim to enhance durability of response, minimize toxicity, and improve survival in HR+/HER2- metastatic breast cancer.

Humans↗
PubMed2026

A critical appraisal of base-resolution m6A profiling techniques.

N6-methyladenosine (m6A) is the most prevalent internal modification in eukaryotic mRNA, influencing RNA fate and gene regulation. Early antibody-based approaches enabled transcriptome-wide profiling but lacked resolution and quantitative accuracy. Newer approaches now achieve base-resolution m6A detection using improved crosslinking, chemical or enzymatic conversion, and single-molecule sequencing. Antibody-free methods provide quantitative stoichiometry from minimal input, while nanopore direct RNA sequencing offers real-time, single-molecule readouts across entire transcriptomes. Collectively, these methods form a versatile toolkit that integrates global mapping with precise site-level analysis, advancing knowledge of context-dependent m6A regulation in physiology and disease. This review compares their principles, strengths, and limitations to guide method selection and highlight how next-generation epitranscriptomic tools are paving the way for clinical and therapeutic applications.

Humans↗
PubMed2026

Programmable enzymes for targeted gene insertion.

Genome editing technologies have advanced from nuclease-based reagents that generate programmed DNA double-strand breaks, which can cause deleterious effects, to next-generation reagents that perform controlled DNA modification through double-strand break-independent mechanisms, such as base editing and prime editing. Although these approaches enable precise small-scale sequence changes, methods for programmable insertion of large DNA cargos have been limited. The ability to write entire genes or large regions into the genome could transform the treatment of genetically heterogeneous disorders, for which numerous pathogenic variants underlie a common disease and mutation-specific editing strategies are impractical. Recent advances in computational genome mining have accelerated the discovery of naturally occurring enzymes with novel biochemical and functional properties, including recombinases and transposases capable of large-scale modifications. Moreover, directed evolution, rational engineering and expanded homologue discovery are enabling the repurposing and optimization of these systems for genome engineering. Here we review recent technology development efforts that harness diverse enzymes for kilobase-scale genome engineering, with a particular focus on CRISPR-associated transposase systems.

Journal Article↗
PubMed2026

Molecular biology and integrated strategies for activating cryptic biosynthetic gene clusters toward next-generation antibiotic discovery.

Antimicrobial resistance (AMR) has been identified as one of the 21st century's severest global public health crises. AMR led to an estimated 4.95 million deaths in 2019 and will claim 10 million lives a year by 2050 in the absence of targeted interventions. During the same period, the number of novel antibiotics discovered has decreased drastically as many researchers are rediscovering known antibiotics, non-model microorganisms are poorly understood or difficult to culture and antibiotic research and development investment has declined drastically. However, high-throughput whole genome sequencing and the subsequent application of bioinformatics in bacterial and fungal genomes have shown that a numerous of cryptic or silent biosynthetic gene clusters (BGCs) remain latent at ambient laboratory conditions since their genes are transcriptionally inactive. Cryptic BGCs represent a vast source of unique secondary metabolites, many of which may yield novel antibacterial, antifungal, anti-cancer and other potentially valuable natural products. This review discusses the biological relevance of cryptic BGCs, the major limiting factors that restricts their activation and novel strategies that have been employed to activate them and exploit their potential to produce novel natural products. The review focuses on biological approaches including CRISPR-Cas mediation for the activation of cryptic BGCs, promoter engineering, pathway refactoring, and heterologous expression; biochemical strategies such as Osman, OsMAC, Precursor Feeding, Chemical Elicitation, Epigenetic Regulation and Co-cultivation and technology-based strategies such as Genome mining, Microfluidic Cultivation systems, High-Throughput Screening, Metabolomics, Molecular Networking and Artificial Intelligence and Machine Learning based prediction of BGCs and their metabolites. The use of multi-omics technologies combined with synthetic biology to achieve better discovery, characterization and large-scale production of novel natural products is also discussed herein. Finally, we will talk about the ecological significance and evolutionary advantage of cryptic BGCs' role in interactions between microorganisms, such as competition, communication, symbiosis and environmental adaptability, so as to provide a useful background for accelerating next-generation antibiotics.

CRISPR-Cas activation↗
PubMed2026

Developing low-carbon metered-dose inhalers: effects of propellant HFA-152a on mucociliary clearance and bronchoconstriction in two Phase 1 randomised trials.

BACKGROUND: To reduce the impact of respiratory care on climate change, metered-dose inhalers (MDIs) are being reformulated with low-global warming potential (GWP) propellants. Next-generation propellant hydrofluoroalkane (HFA)-152a has >90% lower GWP than HFA-134a. As part of the safety evaluation for HFA-152a, mucociliary clearance (MCC), bronchoconstriction and safety were compared with HFA-134a. METHODS: Two Phase 1, randomised, two-way crossover studies (NCT06506266/NCT06702462) were conducted. MCC study: healthy participants inhaled HFA-152a and HFA-134a in two 7-day sequences. MCC was quantified as area under radiolabelled particle retention time curve over 4 h (AUC0-4h) after nebulised 99mTc sulphur colloid, following each propellant. Bronchoconstriction study: patients with mild asthma inhaled single doses of HFA-152a and HFA-134a. Non-inferiority of HFA-152a versus HFA-134a was defined as percent change in FEV1 (litres), 15 min post dose (95% confidence intervals [CI]: lower limit >-10%, upper limit >0%). Both studies assessed safety. RESULTS: In 22 healthy participants, the impact on MCC did not differ between HFA-134a and HFA-152a (AUC0-4h geometric mean ratio [90% CI]: 1.00 [0.99, 1.01]). In 19 patients with mild asthma, neither HFA-152a nor HFA-134a induced bronchoconstriction (percent change in FEV1 at 15 min: -0.37% [HFA-152a] vs -0.60% [HFA-134a]); HFA-152a was non-inferior to HFA-134a (mean difference [95% CI]: 0.23% [-3.61, 4.07]). Adverse event (AE) rates were low and similar for both propellants in both studies; all AEs were mild, with no serious AEs or deaths. CONCLUSION: HFA-152a and HFA-134a had almost identical effects on MCC, neither induced bronchoconstriction, supporting MDI reformulation with the low-GWP propellant HFA-152a.

Humans↗
PubMed2026

A novel allele of Sh1 facilitates the development of waxy-sweet corn from waxy corn.

Waxy corn and sweet corn represent 2 major classes of fresh-eating corn, each with distinct sensory attributes and nutritional compositions. Developing a new variety that combines both waxy and sweet traits would address rising consumer demand and expand new market potential. From a fast neutron-mutagenized population of the waxy corn inbred line HB522, we isolated a novel mutant, designated as wx-sweet, whose kernels simultaneously exhibit waxy and sweet characteristics at the milk-filling stage. Through bulked segregant analysis combined with fine mapping, we mapped the causal locus to SHRUNKEN1 (Sh1) on chromosome 9, which was confirmed by an allelism test with a characterized Mu-insertion allele of Sh1. A 7,227-bp Copia-type long terminal repeat retrotransposon insertion was identified in exon 2 of Sh1 in the wx-sweet mutant by long-read sequencing. Consistently, the novel sh1 allele significantly reduced sucrose synthase activity. Genetic and physiological analyses demonstrate that sh1 and wx1 act synergistically to fine-tune carbohydrate metabolism in the endosperm. Integrated transcriptomic and metabolomic profiling uncover extensive transcriptional reprogramming and redirected metabolic flux, leading to substantial accumulation of sucrose and a range of oligosaccharides. These metabolic shifts underlie the unique simultaneous dual waxy-sweet texture in fresh-eating wx-sweet kernels. In summary, our work not only provides valuable genetic resources for breeding next-generation fresh-eating corn but also, for the first time, elucidates the molecular mechanism by which the sh1 and wx1 mutations cooperatively shape the waxy-sweet endosperm phenotype.

Zea mays↗
PubMed2026

Plant cis-regulatory grammar: Decoding the multidimensional code of transcriptional regulation for programmable crop engineering.

Cis-regulatory elements (CREs) orchestrate the spatiotemporal precision of gene expression that underlies plant development, adaptation, and domestication. Decoding the cis-regulatory grammar of plant genomes remains a central challenge in modern biology, with profound implications for programmable crop engineering. Here, recent conceptual and technological advances are synthesized to reshape our understanding of plant CREs. This review first argues that CRE function is not only an intrinsic property of DNA sequence alone but also emerges from a multidimensional context, including chromatin accessibility, histone modifications, three-dimensional genome topology, and cell type-specific regulatory landscapes. Furthermore, the convergence of single-cell epigenomics, high-throughput functional assays, and CRISPR-based dissection has begun to unravel this contextual grammar, revealing the computational principles governing transcriptional regulation. Critically, we propose that artificial intelligence (AI) platforms are catalyzing an ongoing transition from descriptive discovery to predictive engineering, wherein these platforms outperform natural evolution in designing synthetic CREs. Finally, a roadmap is outlined toward a plant regulatory grammar foundation model, which will enable truly predictive engineering of gene expression when fine-tuned for specific tasks. Collectively, the integration of single-cell resolution maps, precise genome editing, AI-driven design, and regulatory-compliant delivery systems promises to transform our ability to reprogram plant gene regulation for next-generation agriculture, bridging the gap between foundational regulatory biology and tangible crop improvement.

artificial intelligence↗
PubMed2026

Epigenetic Reprogramming and Zygotic Genome Activation in Human Preimplantation Development: Mechanisms, Models, and Translational Prospects.

PURPOSE: Early human embryogenesis unfolds through a tightly coupled sequence of events-clearance of maternal transcripts, remodeling of parental chromatin, zygotic genome activation (ZGA), lineage segregation, implantation, and post-implantation patterning-accompanied by epigenetic reprogramming, including X-chromosome dosage compensation around the time of implantation. This review aims to synthesize recent advances in understanding this developmental program and to consider their implications for reproductive medicine. METHODS: I review recent literature on human early embryogenesis, with particular emphasis on findings enabled by single-cell genomics and stem-cell-based embryo modeling, and integrate these insights to identify human-specific features of early development. RESULTS: These approaches have made previously inaccessible aspects of human early embryogenesis experimentally tractable, revealing molecular and epigenetic features that distinguish human development from that of model organisms, including species-specific dynamics of ZGA, maternal transcript clearance, chromatin reprogramming, and X-chromosome dosage compensation. CONCLUSIONS: Advances in single-cell genomics and embryo modeling are transforming our understanding of human early embryogenesis. Building on these insights, while recognizing their current limitations, I propose a vision for improving reproductive medicine, including the potential for next-generation embryo selection strategies.

Journal Article↗