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PubMed2026

The role of transposable elements-endogenous retroviruses in embryonic development and regeneration.

Endogenous retroviruses (ERVs) are dynamically regulated across the lifespan and can function as context-dependent components of host gene-regulatory networks. During embryonic development, selected ERV-derived elements are co-opted to support zygotic genome activation, lineage specification, and placental development. In adult tissues, ERV-derived sequences can contribute to tissue and immune homeostasis, whereas potentially disruptive ERV activity is constrained by epigenetic mechanisms. During regeneration and somatic cell reprogramming, ERV and broader transposable-element programs undergo transient, locus-specific remodeling. In aging, the weakening of epigenetic and nuclear restraint can promote aberrant ERV derepression, inflammation, and functional decline. This review summarizes the diverse roles of ERVs across these contexts and discusses the challenges of defining locus-specific functions, resolving repetitive sequences, and developing safe ERV-targeted interventions.

Endogenous Retroviruses↗

PubMed2027

Generation of Transgene-Free Naive Human Induced Pluripotent Stem Cells from Somatic Cells Using a Modified Temperature-Sensitive Sendai Virus System.

The Sendai virus (SeV) vector system offers an efficient, nonintegrating approach to reprogram somatic cells into either naive or primed human induced pluripotent stem cells (iPSCs). Here, we describe a protocol to generate transgene-free naive iPSCs from human dermal fibroblasts (HDFs) and peripheral blood mononuclear cells (PBMCs) using a modified, temperature-sensitive SeV system. The method leverages LMYC in place of cMYC and an optional H1FOO-DD factor to enhance efficiency and uniformity, and employs a controlled temperature shift to facilitate vector clearance.

Humans↗

PubMed2026

FOXC2 and WT1 regulate transcriptional reprogramming during the podocyte response to injury.

Transcriptional reprogramming has an important role in kidney glomerular disease. Using in vivo murine models of podocyte injury, we studied the roles of the FOXC2 and WT1 transcription factors (TFs) in podocyte injury. Podocytes are a crucial cell type of glomeruli, the filtration units of each nephron. Podocyte injury is often the incipient event leading to chronic kidney disease. It is well established that the TFs FOXC2 and WT1 are required in podocytes to maintain the glomerular filtration barrier. Their role in the response to injury is less well understood. Here, we tested the hypothesis that FOXC2 and WT1 act together to mediate transcriptional reprogramming in response to podocyte injury. Similarly to that of WT1, genome-wide FOXC2 binding to target genes is dynamic during the course of injury, initially increasing, but late in injury there is a dramatic decrease in FOXC2 expression and in its binding to target genes. Podocyte-specific inactivation of FoxC2 or Wt1 in adult mice limits the transcriptional response to injury. Correlating FOXC2 and WT1 ChIP-seq analyses demonstrated that they co-bind many genes expressed in podocytes. Thus, reprogramming the transcriptome involves dynamic changes in the binding of FOXC2 and WT1 to their target genes during a reparative injury response.

Animals↗

PubMed2026

Induced Pluripotent Stem Cells in Non-Model Species: Applications and Challenges.

Induced pluripotent stem cells have revolutionized biomedical research-yet the vast majority of life on Earth remains beyond their reach. Non-model species lack the annotated genomes, validated reagents, and species-specific culture infrastructure that make iPSC technology routine in humans and mice, and this infrastructure deficit, compounded by genuine biological differences in pluripotency network architecture across taxa, is what has kept the field narrow. The deep conservation of the core pluripotency network across vertebrates suggests that reprogramming may, in principle, be achievable across a far broader range of species than currently demonstrated-though the extent to which this holds across more divergent taxa remains to be established. This review consolidates current progress and future potential of iPSC technology across five domains: technical reprogramming challenges and advances; conservation applications including genetic rescue, in vitro gametogenesis, and de-extinction; medical applications within a one medicine framework; agricultural applications spanning disease resistance, climate resilience, and cultured meat; and species-specific iPSC-derived systems in ecotoxicology. Throughout, we distinguish what has been demonstrated from what remains aspirational and identify the priorities that will determine whether the iPSC revolution can be extended-rigorously and at scale-beyond model organism research.

Induced Pluripotent Stem Cells↗

PubMed2025

DNA Methylation Analysis by Bisulfite Pyrosequencing of Mouse Embryonic Fibroblasts with Reprogramming Enhanced by Thyroid Hormones.

DNA methylation is a widely studied epigenetic mark which in mammals involves the incorporation of a methyl group to the fifth carbon of cytosines, mainly those belonging to CpG dinucleotides. It has been linked to context-dependent regulatory functions ranging from gene and repetitive DNA silencing to gene body transcriptional activity. Because of its important roles during embryonic development and cell differentiation, DNA methylation can be used to track cell reprogramming by measuring the methylation levels of pluripotency-associated factors. In this scenario, bisulfite pyrosequencing is a simple, robust, and widely used technique which allows for the quantification of DNA methylation levels at small, specific regions of the genome. It involves the amplification and biotin tagging of bisulfite-converted DNA. Single amplified strands are then purified using streptavidin and finally pyrosequenced using a sequencing primer. Thus, it is an ideal method for the quantitative profiling of specific genomic regions, with applications ranging from biomarker discovery and epigenetic clock tracking to omic validation studies.

Animals↗

PubMed2026

Harnessing Endogenous Plasticity Rather than Reprogramming of Mature Cells Will Advance Regenerative Medicine, Cancer Treatment and Rejuvenation.

The successful culture of human embryonic stem (hES) cells from inner cell mass cells of blastocyst stage 'spare' embryos in 1998, followed by induced pluripotent stem (iPS) cells in 2006, which allowed somatic cells to be reprogrammed to pluripotency using the Yamanaka factors, transformed regenerative biology and inspired extensive global efforts towards developing pluripotent stem cell-based applications. However, hES and iPS cells, as well as organoids generated from them, largely retain fetal-like characteristics, which limits their relevance for clinical translation. Concurrently, the prevailing assumption published in leading journals that adult tissues lack endogenous stem cells has led to the belief that mature cells dedifferentiate and reprogram during in vivo regeneration upon chronic injury, and that the appearance of embryonic/fetal markers in diabetes, heart failure, cancer, and many other chronic disease states reflects dedifferentiation of mature cells. We suggest that the prevailing concepts of dedifferentiation and reprogramming, both in vitro and in vivo, require careful re-evaluation. Adult somatic cells possibly do not truly dedifferentiate, neither in vitro nor in vivo. Instead, tissue-resident, pluripotent, very small embryonic-like stem cells (VSELs) in multiple organs account for the observed biology. In vitro "reprogramming" responses to Yamanaka factors likely reflect selective activation and expansion of VSELs/early progenitors rather than the dedifferentiation/ reprogramming of mature adult somatic cells. Likewise, the embryonic/fetal-like signatures reported in multiple disease states including cancer reflect expansion of immature tissue-specific progenitors that arise from VSELs but fail to differentiate normally due to a damaged microenvironment in vivo. Therapeutic strategies involving transplantation of MSCs, MUSE cells, or their secreted exosomes improve disease outcomes, possibly by restoring the damaged niche that supports functional tissue repair by VSELs. Although direct evidence to support this is lacking at present, recognising the central role of VSELs/progenitors and their niche in maintaining tissue homeostasis in vivo could resolve existing roadblocks and guide more effective endogenous regenerative therapies for diseased tissues and age-related dysfunctions.

Humans↗

PubMed2026

Loss of PBRM1 accelerates pancreatic cancer progression by inducing acquisition of mesenchymal phenotype and inflammatory cancer-associated fibroblasts reprogramming.

BACKGROUND: PBRM1 is an important subunit of the SWI/SNF complex, which broadly regulates gene transcription by chromatin remodeling. Genomic alterations of PBRM1 have been found in patients with pancreatic ductal adenocarcinoma (PDAC), but its molecular functions remain unclear. METHODS: Clinical relevance of PBRM1 was analyzed by using human PDAC samples and public genomic datasets. Mice with concomitant pancreas-specific Pbrm1 deletion in Kras-driven genetic PDAC models were generated. Single-cell transcriptomics were performed to determine tumor phenotype and microenvironment reprogramming. RESULTS: Reduction of PBRM1 expression was observed in human PDAC tissues and correlated with poor prognosis and metastasis. Pbrm1 loss promoted ductal metaplasia and delayed epithelial recovery in mice with caerulein-induced pancreatic injury. In PDAC model with either mutant Kras alone or in combination with Trp53 mutation, lack of Pbrm1 markedly accelerated tumor development and progression. Bulk transcriptomics and scRNA-seq identified reprogramming of both tumor compartment with mesenchymal phenotype acquisition and stroma compartment with inflammatory cancer-associated fibroblasts (iCAFs) transformation. Mechanistically, Pbrm1 deletion induced Zeb1 upregulation through epigenetic chromatin remodeling, thereby enhancing epithelial-mesenchymal and basal-like subtype transition. CONCLUSIONS: These findings indicated a tumor-suppressing role of PBRM1 in PDAC. PBRM1-deficient PDAC constitutes a specific subgroup of patients with aggressive phenotype and prognostic significance.

Animals↗

PubMed2026

Super enhancer-driven transcriptional reprogramming promotes abiraterone resistance via neuroendocrine transition and ferroptosis evasion in castration-resistant prostate cancer.

Abiraterone resistance represents a major clinical challenge in the management of castration-resistant prostate cancer (CRPC), yet the epigenetic mechanisms that sustain this resistance remain poorly understood. In particular, how super enhancers (SEs) reprogram transcriptional networks to promote this therapy resistance has not been fully elucidated. Here, by integrating chromatin immunoprecipitation sequencing and transcriptome profiling, we identified aberrantly activated oncogenic SEs that drive the transcriptional upregulation of the transcription factors ELF3 and JUNB in abiraterone-resistance CRPC cells. Importantly, SE-driven activation of the ELF3/JUNB axis promotes abiraterone resistance by inducing WNT11-mediated neuroendocrine transition. In parallel, this transdifferentiated state is closely associated with ferroptosis resistance, as evidenced by the upregulation of key ferroptosis-protective genes, including FTH1 and GPX4. In contrast, disruption of the ELF3/JUNB-WNT11 axis markedly restored abiraterone sensitivity and triggered ferroptotic cell death in CRPC cells both in vitro and in vivo. Collectively, our findings highlight targeting SE-driven transcriptional programs as a promising strategy for overcoming abiraterone resistance in CRPC.

Male↗

PubMed2026

CHCHD10 Mitigates Alzheimer's Disease-Related Phenotypes in Association With Epigenetic Remodeling in Directly Reprogrammed Neurons.

Mitochondrial dysfunction and chromatin dysregulation are interconnected contributors to neuronal vulnerability in Alzheimer's disease (AD), yet the molecular mechanisms linking these processes remain poorly understood. CHCHD10, a mitochondrial intermembrane space protein, has been implicated in neurodegenerative disorders, but its role in AD has not been defined. Here, we identify CHCHD10 as a previously unrecognized modulator of neuronal epigenomic stability in AD. Using direct fibroblast-to-neuron reprogramming, which preserves patient-specific epigenetic signatures, we show that AD neurons recapitulate genome-wide hypomethylation patterns observed in postmortem AD cortex. CHCHD10 expression is significantly reduced in AD neurons and across multiple human brain datasets, including single-cell and bulk RNA sequencing, proteomics, and human cortical tissue analyses. Restoration of CHCHD10 in AD neurons reduces amyloid-β and insoluble tau accumulation while reversing AD-associated differentially methylated regions across CpG islands, promoters, and regulatory elements. CHCHD10-responsive methylation changes overlap with those observed in human AD brain regions and colocalize with significant AD loci and cortex-specific eQTL loci, including MAPT and ABCA7. Finally, we identify KATNAL2 as a CHCHD10-responsive effector whose loss enhances tau phosphorylation and seeding, whereas its restoration mitigates tau pathology. Together, these findings support a CHCHD10-associated neuroprotective pathway linking mitochondrial dysfunction, epigenomic instability, and tau pathology in AD.

Humans↗

PubMed2025

Genome-Wide Silencer Screening Reveals Key Silencer Modulating Reprogramming Efficiency in Mouse Induced Pluripotent Stem Cells.

The majority of the mouse genome is composed of non-coding regions, which harbor numerous regulatory sequences essential for gene regulation. While extensive research focuses on enhancers that activate gene expression, the role of silencers that repress gene expression remains less explored. In this study, the first genome-wide identification of silencers in the mouse genome is conducted. In mouse embryonic fibroblasts (MEFs) and embryonic stem cells (mESCs), 89 596 and 115 165 silencers are identified, respectively. These silencers are ubiquitously distributed across the genome and are predominantly associated with low-expression genes. Additionally, these silencers are mainly cell-specific and function by binding to repressive transcription factors (TFs). Further, these silencers are notably enriched with the histone modification H3K9me3. It is observed that the transformation between dual-function silencers and enhancers is correlated with intracellular transcription factor concentrations, accompanied by changes in epigenetic modifications. In terms of biological effects, we have identified silencers that can enhance the induction efficiency of MEFs and influence the pluripotency of mESCs. Collectively, this work offers the first comprehensive silencer landscape in the mouse genome and provides strong evidence for the role of silencers in the induction of induced pluripotent stem cells (iPSCs).

Animals↗

PubMed2026

Generation of induced pluripotent stem cell line NTUHi003-A from a patient with premature ovarian insufficiency.

Premature ovarian insufficiency (POI) is characterized by impaired ovarian function before 40 years of age and is associated with heterogeneous etiologies. Herein, we established a human induced pluripotent stem cell (hiPSC) line, NTUHi003-A, from the peripheral blood mononuclear cells (PBMCs) of a patient with POI. The generated hiPSC line exhibited a normal 46, XX karyotype and demonstrated confirmed pluripotency. This cell line provides a valuable cellular platform for disease modeling and mechanistic studies of POI.

Humans↗

PubMed2026

IRAK4 constrains cellular plasticity during chemically-induced cell fate reprogramming into multiple lineages.

Chemical reprogramming holds transformative potential for regenerative medicine. However, the regulatory mechanisms governing cell fate transitions are not well understood. Here, we identify Interleukin-1 Receptor-Associated Kinase 4 (IRAK4) as a barrier to multi-lineage reprogramming. Pharmacological inhibition of IRAK4 enhances the reprogramming of mouse embryonic fibroblasts (MEFs) through a chemically activated multi-lineage priming (CaMP) state and extraembryonic endoderm (XEN)-like intermediates, increasing colony formation, and the expression of core XEN regulators (Sox17, Gata4, Sall4, and Foxa2). Genetic knockdown of Irak4 similarly accelerates reprogramming, whereas its overexpression blocks cell fate transitions. IRAK4 inhibition enhances chromatin accessibility and reshapes cell cycle dynamics, characterized by G0/G1 shortening and G2/M lengthening, potentially contributing to multi-lineage state establishment. Furthermore, IRAK4 suppression enhances the direct conversion of MEFs to neuron-like and hepatocyte-like cells, which exhibit enhanced functional maturity, including increased glycogen storage and improved detoxification capacity. Our findings establish IRAK4 as a regulator that constrains cellular plasticity potentially by coordinating chromatin accessibility and cell cycle dynamics.

Animals↗

PubMed2024

Remodeling of cytoskeleton, chromatin, and gene expression during mechanical rejuvenation of aged human dermal fibroblasts.

Aging is associated with a progressive decline in cellular function. To reset the aged cellular phenotype, various reprogramming approaches, including mechanical routes, have been explored. However, the epigenetic mechanisms underlying cellular rejuvenation are poorly understood. Here, we studied the cytoskeletal, genome-wide chromatin and transcriptional changes in young, aged, and mechanically rejuvenated fibroblasts using immunofluorescence, RNA sequencing, and Hi-C experiments. The mechanically rejuvenated aged fibroblasts, that had partially reset their transcription to a younger cell state, showed a local reorganization of the interchromosomal contacts and lamina-associated domains. Interestingly, the observed chromatin reorganization correlated with the transcriptional changes. Immunofluorescence experiments in the rejuvenated state confirmed increased actomyosin contractility like younger fibroblasts. In addition, the rejuvenated contractile properties were maintained over multiple cell passages. Overall, our results give an overview of how changes in the cytoskeleton, chromatin, and gene activity are connected to aging and rejuvenation.

Humans↗

PubMed2026

Matrix Mechanics Governs Mechano-Metabolic Adaptation across Cancer Grades in Bladder Spheroids.

Extracellular matrix (ECM) mechanics is pivotal regulators of tumor progression, yet how viscoelasticity and matrix architecture converge to shape metabolic and invasive adaptation remains insufficiently defined. We postulate that mechanical stimuli from the ECM induce coordinated changes in adhesive and metabolic pathways, and that the nature of this independent mechano-metabolic pathway is conserved across benign, low-invasive, and high-invasive bladder cancer phenotypes. Therefore, we engineered collagen-hyaluronan hydrogels with tunable stiffness to recapitulate soft and rigid tumor microenvironments and profiled bladder cancer spheroids representing benign, low-invasive, and highly invasive states. Integrating hydraulic force spectroscopy, rheology, and molecular phenotyping, we show that matrix stiffening differentially reprograms spheroid architecture, motility, and adhesion- and metabolism-related gene expression. Spheroid behavior emerged from the interplay between intrinsic mechanical properties, matrix rheology, and molecular adaptation. HCV29 spheroids formed rigid, compact structures, relying on cell-matrix adhesion rather than metabolic or proteolytic remodeling. HT1376 spheroids activated glycolysis (HK2) and MMP-2-dependent ECM remodeling in soft matrices, but remained largely nonmigratory, indicating decoupling of invasive priming from motility. T24 spheroids were soft, deformable, and highly migratory in compliant matrices, integrating metabolic reprogramming, adhesion remodeling (E-/N-cadherin, SDC4), and radial collagen fiber alignment to drive invasion. Notably, canonical FAK/AKT/mTOR signaling was absent across all spheroids, while pS6 ribosomal protein and ILK indicated noncanonical, SDC4/integrin-ILK-dependent mechanotransduction supporting cytoskeletal dynamics, metabolism, and ECM remodeling. Collagen organization further differed across spheroid types, with dense, radially aligned fibers in HT1376, intermediate architecture in HCV29, and loose, disorganized networks in T24, closely matching their distinct migratory behaviors and cell-ECM interactions. These findings reveal stage-specific mechanometabolic strategies in bladder cancer, demonstrating how ECM mechanics and architecture jointly guide invasion, metabolic adaptation, and local immune modulation, including the regulation of immune cell infiltration and tumor immune evasion.

Humans↗

PubMed2026

Characterization of DNA methylation in PBMCs and donor-matched iPSCs shows age-related methylation is reset during stem cell reprogramming.

DNA methylation is an important epigenetic mechanism that helps define and maintain cellular functions. It is influenced by many factors, including environmental exposures, genotype, cell type, sex, and aging. Since age is the primary risk factor for developing neurodegenerative diseases, it is important to determine if age-related DNA methylation is retained when cells are reprogrammed to an induced Pluripotent Stem Cell (iPSC) state. Here, we selected peripheral blood mononuclear cells (PBMCs; n = 99) from a cohort of diverse and healthy individuals enrolled in the Genetic and Epigenetic Signatures of Translational Aging Laboratory Testing (GESTALT) study to reprogram to iPSCs. After reprogramming, the resulting iPSCs were evaluated for DNA methylation signatures to determine if they reflect the confounding factors of aging and environmental effects. Data from genome-wide DNA methylation arrays in both cell types showed that age-related methylation measured by epigenetic clocks is largely reset to an early methylation age after reprogramming of PBMCs to iPSCs. We further examined the epigenetic age of each cell type using an Epigenome-wide Association Study (EWAS) and identified a set of methylation Quantitative Trait Loci in each cell type. Our results show that age-related DNA methylation is largely reset in iPSCs, and each cell type has a unique set of methylation sites that are modified by population-level genetic variation.

DNA Methylation↗

PubMed2025

Genome-wide CRISPR screens identify critical targets to enhance CAR-NK cell antitumor potency.

Adoptive cell therapy using engineered natural killer (NK) cells is a promising approach for cancer treatment, with targeted gene editing offering the potential to further enhance their therapeutic efficacy. However, the spectrum of actionable genetic targets to overcome tumor and microenvironment-mediated immunosuppression remains largely unexplored. We performed multiple genome-wide CRISPR screens in primary human NK cells and identified critical checkpoints regulating resistance to immunosuppressive pressures. Ablation of MED12, ARIH2, and CCNC significantly improved NK cell antitumor activity against multiple treatment-refractory human cancers in vitro and in vivo. CRISPR editing augmented both innate and CAR-mediated NK cell function, associated with enhanced metabolic fitness, increased secretion of proinflammatory cytokines, and expansion of cytotoxic NK cell subsets. Through high-content genome-wide CRISPR screening in NK cells, this study reveals critical regulators of NK cell function and provides a valuable resource for engineering next-generation NK cell therapies with improved efficacy against cancer.

Humans↗

PubMed2026

Lipid reprogramming of stratified squamous epithelium by the high-risk HPV E6 and E6/E7 oncoproteins.

INTRODUCTION: High risk human papillomavirus (HPV) infection and genome integration with pronounced expression of the viral E6/E7 oncogenes is the major cause of cervical cancer. Emerging evidence suggests that HPV reprograms host metabolism to support viral persistence and cellular transformation. However, global HPV oncogene-induced lipidomic reprogramming remains poorly understood, particularly at early stages of HPV-induced transformation. OBJECTIVE: We sought to define the regulation of lipid metabolism in squamous epithelia of transgenic mice expressing the HPV16 oncogene E6 alone or in conjunction with E7. METHODS: Untargeted lipidomics was used to identify novel lipid biomarkers in the skin and female reproductive tract (FRT) of HPV16 E6 and E6/E7 transgenic compared to wild-type (WT) mice. To investigate enzymatic dysregulation of lipids by HPV oncogene expression, we employed Lipid Network Explorer (LINEX2), which analyzes lipidomics data through lipid enrichment analysis. We also used the Global Natural Product Social Molecular Networking (GNPS) platform to enhance lipid identification, exploring molecular networking to improve feature annotation. RESULTS: Our lipidomic analysis produced several new observations. First, E6 expression caused a consistent alteration of glycerophospholipids, with particularly significant substrate-product shifts in the phosphatidylcholine (PC) to lysophosphatidylcholine (LPC) pathway in the skin. Second, E6/E7 expression caused a dysregulation of glucosylceramide (GlcCer) biosynthesis. Third, both E6/E7 expressing skin and FRT tissues exhibited a redox imbalance and increased levels of oxidized lipids, including oxylipins and several oxidized PCs. These findings suggest that HPV oncoproteins drive lipid reprogramming, potentially contributing to early HPV-related tumorigenesis. CONCLUSIONS: These findings provide new insights into HPV‑induced lipid reprogramming and establish a framework for future studies examining the functional and clinical relevance of lipid alterations in HPV‑associated cancers.

Animals↗

PubMed2026

Lactylome Reprogramming Mediates Therapeutic Response and Adaptation to Neoadjuvant Chemotherapy in Esophageal Squamous Cell Carcinoma.

Esophageal squamous cell carcinoma (ESCC) exhibits high prevalence in China and poor prognosis despite neoadjuvant chemotherapy (NACT), with significant chemoresistance development. Tumor-associated metabolic reprogramming and NACT-induced cellular stress promote lactate accumulation, which serves as a precursor for lysine lactylation (Kla), a post-translational modification potentially regulating cancer progression. We hypothesized that systematic characterization of the lactylome in response to NACT could reveal critical molecular mechanisms underlying treatment and identify new therapeutic vulnerabilities in ESCC. Herein, through comprehensive proteomic and lactylome profiling of tumor and adjacent normal adjacent tissues from 31 ESCC patients (with or without NACT treatment), we identified 8281 proteins and 1836 Kla sites across 62 samples. NACT induced substantial lactylome alterations with 307 differentially expressed Kla sites predominantly in nonhistone proteins involved in DNA damage response and metabolic pathways. Our data revealed that while NACT-induced suppression of energy metabolism, coupled with upregulated 3-hydroxy-3-methylglutaryl reductase degradation 1 complex expression, may exert potential proapoptotic effects, the activation of ribosome biogenesis and increased nucleoprotein lactylation triggered tumor-protective mechanisms. Mechanistically, we demonstrated that DNA damage and elevated lactate levels induced poly(ADP-ribose) polymerase 1 K654 lactylation, enhancing its enzymatic activity and augmenting poly(ADP-ribosyl)ation of downstream targets, potentially playing a pivotal role in chemotherapy resistance-associated pathways. This comprehensive tissue-level landscape of Kla dynamics in ESCC response to chemotherapy establishes Kla as a critical regulatory mechanism in treatment response, potentially offering novel therapeutic targets and predictive biomarkers for personalized treatment strategies.

Humans↗