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PubMed2026

Reciprocal, methylation-dependent binding of Zfp57 and Gzf1 safeguards Dlk1-Dio3 imprinting during developmental reprogramming.

Genomic imprinting secures parent-specific gene expression through differential DNA methylation at imprinted control regions (ICRs). However, how unmethylated alleles resist de novo methylation remains unclear. Using an allelic Dlk1-Dio3 ICR methylation reporter and genome-wide loss-of-function screening, we identify the zinc finger protein GZF1 that binds the unmethylated maternal ICR and protects it from de novo methylation via a regulatory element containing GZF1 and ZFP57 motifs that mediates mutually exclusive, methylation-dependent binding. Loss of either factor causes reciprocal imprinting failure: Gzf1 loss induces maternal allele methylation, H3K4me3 depletion, and silencing of maternal transcripts, whereas Zfp57 loss results in maternalization. Remarkably, GZF1 protects the unmethylated ICR from de novo methylation in both oocytes and embryos, and its loss leads to perinatal death consistent with paternalization of the maternal allele. Together, our findings establish a reciprocal mechanism that maintains parental epigenetic asymmetry across both imprint establishment and embryonic reprogramming.

Animals↗
PubMed2006

Sequential valproic acid/all-trans retinoic acid treatment reprograms differentiation in refractory and high-risk acute myeloid leukemia.

Epigenetic alterations of chromatin due to aberrant histone deacetylase (HDAC) activity and transcriptional silencing of all-trans retinoic acid (ATRA) pathway are events linked to the pathogenesis of acute myeloid leukemia (AML) that can be targeted by specific treatments. A pilot study was carried out in eight refractory or high-risk AML patients not eligible for intensive therapy to assess the biological and therapeutic activities of the HDAC inhibitor valproic acid (VPA) used to remodel chromatin, followed by the addition of ATRA, to activate gene transcription and differentiation in leukemic cells. Hyperacetylation of histones H3 and H4 was detectable at therapeutic VPA serum levels (>or=50 microg/mL) in blood mononuclear cells from seven of eight patients. This correlated with myelomonocytic differentiation of leukemic cells as revealed by morphologic, cytochemical, immunophenotypic, and gene expression analyses. Differentiation of the leukemic clone was proven by fluorescence in situ hybridization analysis showing the cytogenetic lesion +8 or 7q- in differentiating cells. Hematologic improvement, according to established criteria for myelodysplastic syndromes, was observed in two cases. Stable disease and disease progression were observed in five and one cases, respectively. In conclusion, VPA-ATRA treatment is well tolerated and induces phenotypic changes of AML blasts through chromatin remodeling. Further studies are needed to evaluate whether VPA-ATRA treatment by reprogramming differentiation of the leukemic clone might improve the response to chemotherapy in leukemia patients.

Antineoplastic Agents↗
PubMed2006

The epigenetic network regulating muscle development and regeneration.

This review focuses on our current knowledge of the epigenetic changes regulating gene expression at the chromatin and DNA level, independently on the primary DNA sequence, to reprogram the nuclei of muscle precursors during developmental myogenesis and muscle regeneration. These epigenetic marks provide the blueprint by which the extra-cellular cues are interpreted at the nuclear level by the transcription machinery to select the repertoire of tissue-specific genes to be expressed. The reversibility of some of these changes necessarily reflects the dynamic nature of skeletal myogenesis, which entails the progression through two antagonistic processes--proliferation and differentiation. Other epigenetic modifications are instead associated to events conventionally considered as irreversible--e.g. maintenance of lineage commitment and terminal differentiation. However, recent results support the possibility that these events can be reversed, at least upon certain experimental conditions, thereby revealing a dynamic nature of many of the epigenetic modifications underlying skeletal myogenesis. The elucidation of the epigenetic network that regulates transcription during developmental myogenesis and muscle regeneration might provide the information instrumental to devise pharmacological interventions toward selective manipulation of gene expression to promote regeneration of skeletal muscles and possibly other tissue.

Animals↗
PubMed1984

The biological significance of meiosis.

Four possible biological functions of meiosis are considered. First, the conventional view that it generates by recombination and sexual reproduction the genetic diversity on which natural selection can act. Second, that recombination at meiosis plays an important role in the repair of genetic defects in germ line cells. Third, that it is essential, at least in animals, for the reprogramming of gametes which give rise to the fertilized egg. Fourth, that it helps maintain the immortality of the germ line, possible by a process of rejuvenation involving the removal of faulty RNA and protein molecules, or by the elimination of defective meiocytes. A unified hypothesis is proposed which attempts to link these diverse functions. Evidence is now available which strongly indicates that the control of gene activity in higher organisms depends in part on the pattern of cytosine methylation in DNA, and that this pattern is inherited through the activity of a maintenance methylase. Epigenetic defects may arise by the loss of methyl groups which the methylase is unable to replace in somatic and also germ line cells, if de novo methylation cannot occur. There is also evidence that recombination at meiosis is largely confined to structural genes or adjacent DNA. It is proposed that the absence of a functionally important methyl group in a promotor or operater region produces a recombinator or signal for the initiation of recombination. The formation of hybrid DNA in this region then allows the lost methyl groups to be replaced by maintenance methylase activity. The removal of epigenetic defects by recombination during meiosis therefore becomes an essential part of a reprogramming and rejuvenation process. Assuming some epigenetic defects are nevertheless transmitted to the next generation, sexual reproduction and outbreeding would be advantageous because they provide the opportunity for their removal at the next meiosis. Inbreeding would be disadvantageous, because it increases the probability that epigenetic defects would become homozygous and could no longer be removed by recombination.

5-Methylcytosine↗
PubMed2005

Epigenetic memory of active gene transcription is inherited through somatic cell nuclear transfer.

The transplantation of somatic cell nuclei to enucleated eggs has shown that genes can be reprogrammed to an embryonic pattern of expression, thereby indicating a reversal of their epigenetic state. However, in Xenopus nuclear transfer experiments using both endoderm and neuroectoderm donor cells, we have observed substantial overexpression of donor cell type-specific genes, both spatially and temporally, in the wrong cell type in some nuclear transplant embryos. For example, more than half of the embryos prepared from transplanted neuroectoderm nuclei overexpressed the neuroectodermal marker gene Sox2 to an excessive level in their endoderm cells. Because, in Xenopus, there is no transcription for the first 12 cell cycles, some somatic cell nuclei must remember a developmentally activated gene state and transmit this to their mitotic progeny in the absence of the conditions that induced that state. We also find that donor cell-specific genes are transcribed at an earlier stage than normal in an inappropriate cell type. This phenomenon of epigenetic memory applies to genes that are transcribed in donor nuclei; it does not influence those genes that are competent to be transcribed in nuclear transplant embryo tissue, but were not actually transcribed in donor nuclei at the time of nuclear transfer. We conclude that an epigenetic memory is established in differentiating somatic cells and applies to genes that are in a transcriptionally active state.

Animals↗
PubMed2026

Induced pluripotent stem cell reprogramming: methodological evolution and challenges in clinical translation.

Cell reprogramming can transform somatic cells into induced pluripotent stem cells providing a platform for patient-specific disease modeling, drug screening and regenerative medicine research. Since the advent of OKSM-mediated reprogramming, the system of technical approaches has evolved continuously - from integrated viral vectors to non-integrated episomal systems and, more recently, chemical reprogramming and CRISPR approaches. The simultaneous advances in single-cell multi-omics, biomaterials engineering, and artificial intelligence have further refined the controllability and precision of the reprogramming process. Despite these innovations, problems persist that hinder clinical translation: incomplete epigenetic resetting, ongoing clonal heterogeneity, genomic instability in long-term culture, and the lack of standardized Good Manufacturing Practice protocols for large-scale manufacturing. This review summarizes the trajectory of iPSC reprogramming technologies, with special emphasis on the translational applicability of each modality. We evaluated viral and nonviral delivery systems, chemical reprogramming, strategies that aid gene editing, and emerging engineering platforms, including microfluidics, smart biomaterials, and artificial-intelligence-driven process optimization. We further identify the core "translational triltrilas", namely, the inherent tradeoffs between security, homogeneity, and scalability, and propose a comprehensive strategy to overcome these bottlenecks. By linking basic mechanistic understandings with industrial and regulatory considerations, this review aims to provide a route for transitioning iPSC technology from a laboratory tool to a clinically viable manufacturing platform.

clinical translation↗
PubMed2024

DNA methylation reprogramming in teleosts.

Early embryonic development is crucially important but also remarkably diverse among animal taxa. Axis formation and cell lineage specification occur due to both spatial and temporal control of gene expression. This complex system involves various signaling pathways and developmental genes such as transcription factors as well as other molecular interactants that maintain cellular states, including several types of epigenetic marks. 5mC DNA methylation, the chemical modification of cytosines in eukaryotes, represents one such mark. By influencing the compaction of chromatin (a high-order DNA structure), DNA methylation can either repress or induce transcriptional activity. Mammals exhibit a reprogramming of DNA methylation from the parental genomes in the zygote following fertilization, and later in primordial germ cells (PGCs). Whether these periods of methylation reprogramming are evolutionarily conserved, or an innovation in mammals, is an emerging question. Looking into these processes in other vertebrate lineages is thus important, and teleost fish, with their extensive species richness, phenotypic diversity, and multiple rounds of whole genome duplication, provide the perfect research playground for answering such a question. This review aims to present a concise state of the art of DNA methylation reprogramming in early development in fish by summarizing findings from different research groups investigating methylation reprogramming patterns in teleosts, while keeping in mind the ramifications of the methodology used, then comparing those patterns to reprogramming patterns in mammals.

Animals↗
PubMed2001

Nuclear transfer in human medicine and animal breeding.

Cloning has a number of potential applications in human medicine and animal breeding, but the efficiency of production of developmentally competent embryos and healthy animal offspring needs to be improved. The primary deficiency appears to be incomplete or abnormal nuclear reprogramming after nuclear transfer, and it is hypothesized that epigenetic regulators of transcription cannot always be converted to the embryonic pattern and this leads to implantation failure, gestational abnormalities and poor health of offspring. Research needs to be focused on this aspect of development for nuclear transfer embryos. However, there is a gradual demand for commercial application for cloning in animal production, transgenesis and animal biopharmaceuticals, particularly in milk. These applications will expand in the near future. There is little application of nuclear transfer in human medicine at present, but important applications may be demonstrated for prevention of the inheritance of mitochondrial mutations, prevention of age-related aneuploidis in women, artificial gametes for sterile individuals or couples and for therapeutic cloning to enable cell and gene therapies.

Animal Husbandry↗
PubMed2026

Spatial niche remodeling of senescent liver-resident immune cells and its role in chronic liver diseases.

The liver serves the triple functions of metabolism, detoxification, and immune surveillance. Its unique immune microenvironment is shaped by continuous exposure to gut-derived antigens, pathogen-associated molecular patterns (PAMPs), and metabolites arriving via the portal vein, necessitating a delicate equilibrium between immune tolerance and effector activation. This equilibrium relies on the coordinated activities of diverse liver-resident immune cell populations-including Kupffer cells (KCs), liver sinusoidal endothelial cells (LSECs), hepatic stellate cells (HSCs), dendritic cells (DCs), tissue-resident memory T cells (TRM), innate-like T cells, including mucosal-associated invariant T (MAIT) cells, natural killer T (NKT) cells, and γδ T cells, innate lymphoid cells (ILCs, encompassing conventional NK cells and helper ILC subsets), and neutrophils. With advancing age and chronic injury, these resident immune cell populations undergo profound senescence-associated phenotypic reprogramming that is spatially organized along the portal-to-central axis of the hepatic lobule. Key mechanisms include: telomere dysfunction and DNA damage accumulation driving persistent activation of p53/p21 and p16/Rb pathways; mitochondrial dysfunction with mitochondrial DNA (mtDNA) leakage fueling the senescence-associated secretory phenotype (SASP) via the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway; epigenetic age acceleration, including genome-wide H3K27me3 heterochromatinization; and metabolic reprogramming toward glycolysis and lipid accumulation. This review proposes a "spatial niche remodeling" framework to integrate these cell-intrinsic senescence programs with their lobular context, intercellular communication network rewiring, and pathogenic roles across the spectrum of chronic liver disease-from steatosis through steatohepatitis, fibrosis, cirrhosis, to hepatocellular carcinoma. We critically evaluate emerging senotherapeutic strategies targeting specific liver-resident immune cell subsets, discuss the barriers to clinical translation, and identify priority areas for future investigation, including the application of spatial multi-omics, humanized models, and epigenetic clock-guided clinical trials.

Kupffer cells↗
PubMed2006

Circular chromosome conformation capture (4C) uncovers extensive networks of epigenetically regulated intra- and interchromosomal interactions.

Accumulating evidence converges on the possibility that chromosomes interact with each other to regulate transcription in trans. To systematically explore the epigenetic dimension of such interactions, we devised a strategy termed circular chromosome conformation capture (4C). This approach involves a circularization step that enables high-throughput screening of physical interactions between chromosomes without a preconceived idea of the interacting partners. Here we identify 114 unique sequences from all autosomes, several of which interact primarily with the maternally inherited H19 imprinting control region. Imprinted domains were strongly overrepresented in the library of 4C sequences, further highlighting the epigenetic nature of these interactions. Moreover, we found that the direct interaction between differentially methylated regions was linked to epigenetic regulation of transcription in trans. Finally, the patterns of interactions specific to the maternal H19 imprinting control region underwent reprogramming during in vitro maturation of embryonic stem cells. These observations shed new light on development, cancer epigenetics and the evolution of imprinting.

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

Integrative analysis of transcriptome and DNA methylome dynamics during caudal fin regeneration in silver pomfret (Pampus argenteus).

Caudal fin regeneration in teleost fish is a complex, multi-stage process involving coordinated molecular and cellular changes. While the role of epigenetic regulation particularly DNA methylation has been studied in model freshwater species such as zebrafish, its contribution to regeneration in marine teleosts remains largely unexplored. In this study, we integrated transcriptomic and DNA methylomic data to characterize the temporal dynamics of gene expression and methylation during caudal fin regeneration in the silver pomfret (Pampus argenteus). Using RNA-sequencing and reduced representation bisulfite sequencing (RRBS) at three biologically critical time points 1, 3, and 7 days post-amputation (dpa), we characterized the spatiotemporal molecular landscape of caudal fin regeneration. These time points capture the key transitional phases of wound healing and inflammation (1 dpa), blastema formation and progenitor proliferation (3 dpa), and regenerative outgrowth with tissue remodeling (7 dpa), enabling robust detection of the major molecular programs underlying epimorphic regeneration. Concurrently, CG-methylome analysis identified thousands of dynamically changing differentially methylated regions (DMRs). A strong global inverse correlation was observed between promoter methylation and gene expression. Integrative analysis pinpointed key regeneration genes (fgf20a, msxb, sox9b) whose expression was associated with dynamic methylation changes in their promoters or gene bodies. We conclude that DNA methylation is a dynamic and key regulatory layer that acts in concert with transcriptional reprogramming to coordinate tissue regeneration, providing new insights into the epigenetic mechanisms underlying complex regenerative processes in teleosts.

Animals↗
PubMed2004

DNA methylation in the preimplantation embryo: the differing stories of the mouse and sheep.

In mammals, active demethylation of cytosine methylation in the sperm genome prior to forming a functional zygotic nucleus is thought to be a function of the oocyte cytoplasm important for subsequent normal development. Furthermore, a stepwise passive loss of DNA methylation in the embryonic nucleus has been observed as DNA replicates between two-cell and morula stages, with somatic cell levels of methylation being re-established by, or after the blastocyst stage when differentiated lineages are formed. The ability of oocyte cytoplasm to also reprogram the genome of a somatic cell by nuclear transfer (SCNT) has raised the possibility of directing reprogramming of a somatic nucleus ex ovo by mimicking the epigenetic events normally induced by maternal factors from the oocyte. Whilst examining DNA methylation changes in normal sheep fertilization, we were surprised to observe no demethylation of the sheep male pronucleus at any point in the first cell cycle. Furthermore, using quantitative image analysis, we observed limited demethylation of the sheep embryonic genome only between the two- and eight-cell stages and no evidence of remethylation by the blastocyst stage. We suggest that the dramatic differences in DNA methylation between the sheep and other mammalian species examined call in to question the requirement and role of DNA methylation in early mammalian embryonic development.

Animals↗
PubMed2026

DNA Methylation-Mediated Regulation of TAGLN2 Expression Promotes Pulmonary Arterial Hypertension.

BACKGROUND: Succinylation, a key post-translational modification, is implicated in the metabolic reprogramming and vascular remodeling of pulmonary arterial hypertension (PAH). While epigenetic regulation, particularly DNA methylation, potentially governs succinylation-related gene expression, its causal links to PAH remain unclear. METHODS: We performed an integrative causal analysis using two-sample Mendelian randomization (MR) and summary-data-based MR (SMR) to identify succinylation-related genes that influence PAH risk. We leveraged PAH GWAS data (FinnGen) and gene expression quantitative trait loci (eQTLGen). Subsequently, methylation-mediated effect decomposition was applied using DNA methylation data (GoDMC) to explore epigenetic regulation. Experimental validation was conducted in lung tissues from a monocrotaline (MCT)-induced PAH rat model via quantitative reverse transcription polymerase chain reaction (qRT-PCR). RESULTS: Genetic analyses identified a significant causal effect of elevated Transgelin 2 (TAGLN2) expression on increased PAH risk. This effect was mediated by two specific DNA methylation sites, cg13892570 and cg16107628, which influenced PAH pathogenesis by regulating TAGLN2 transcription, with mediation proportions of 86.46 and 97.65%, respectively. Sensitivity analyses supported the robustness of these findings. Consistent with the genetic evidence, TAGLN2 mRNA was significantly upregulated in the lungs of MCT-induced PAH rats. CONCLUSIONS: This study establishes a clear epigenetic causal pathway in which DNA methylation regulates TAGLN2 expression to promote PAH. TAGLN2 is validated as a key disease driver and presents a promising target for diagnostic and therapeutic strategies in PAH.

Animals↗
PubMed2026

Molecular mechanisms of plant thermal response: from signal transduction and epigenetic regulation to signaling integration.

Global warming intensification elevates heat stress to one of the major threats to crop productivity. This review synthesizes recent advances in understanding the mechanisms governing plant responses to both moderate and acute heat stress, with a focus on the integration of epigenetic regulation and signaling networks that underpin thermal adaptation. This review highlights how transcription factors PHYTOCHROME-INTERACTING FACTOR 4 (PIF4, during thermomorphogenesis) and HEAT SHOCK FACTOR A1s (HSFA1s, in heat shock responses) orchestrate plant adaptive growth through crosstalk among light, circadian, and hormone signaling pathways. Importantly, epigenetic mechanisms, including histone variant H2A.Z dynamics and histone modification reprogramming, function as central regulators of thermal plasticity. Key among these processes are HSFA2-mediated chromatin remodeling and small interfering RNA (siRNA)-dependent control of transgenerational thermomemory. Despite this progress, fundamental questions persist regarding temperature sensing, HSFA1s activation dynamics, and stress signal integration. Multi-omics and synthetic biology approaches are proposed to be pivotal in deciphering conserved principles of plant thermal resilience, ultimately providing a theoretical foundation and molecular breeding strategies for climate-smart crops.

Epigenesis, Genetic↗
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↗
PubMed2005

Epigenetic transdifferentiation of normal melanocytes by a metastatic melanoma microenvironment.

The clinical management of cutaneous melanoma would benefit significantly from a better understanding of the molecular changes that occur during melanocytic progression to a melanoma phenotype. To gain unique insights into this process, we developed a three-dimensional in vitro model that allows observations of normal human melanocytes interacting with a metastatic melanoma matrix to determine whether these normal cells could be reprogrammed by inductive cues in the tumor cell microenvironment. The results show the epigenetic transdifferentiation of the normal melanocytic phenotype to that of an aggressive melanoma-like cell with commensurate increased migratory and invasive ability with no detectable genomic alterations. Removal of the transdifferentiated melanocytes from the inductive metastatic melanoma microenvironment results in a reversion to their normal phenotype. However, a normal melanocyte microenvironment had no epigenetic influence on the phenotype of metastatic melanoma cells. This novel approach identifies specific genes involved in the transdifferentiation of melanocytes to a more aggressive phenotype, which may offer significant therapeutic value.

Cell Differentiation↗
PubMed2026

Transcription regulation of cell fate plasticity - from embryonic development to tissue regeneration.

Cell fate plasticity refers to the capacity of cells sharing the same genome to alter, reverse, or reconfigure their identity under physiological, pathological, or experimental conditions. This property underlies embryonic development, cellular reprogramming, and tissue regeneration, but becomes progressively restricted as lineage identity is stabilized. Embryonic development represents an intrinsic process of fate transitions, whereas reprogramming and regeneration reveal how differentiated cells can dedifferentiate or transdifferentiate under specific conditions. Across these contexts, plasticity is governed by multilayered regulatory networks involving transcription factors, epigenetic regulators, cofactors, and the core transcription machinery. Robust regulatory programs stabilize cell identity, whereas stochastic fluctuations in gene expression and chromatin state can prime cells for fate transitions, adding a tunable dimension to plasticity control. In this review, we synthesize recent advances in the regulation of cell fate plasticity across development, reprogramming, and regeneration, highlighting how transcription factors, epigenetic modifications, transcriptional cofactors, and core transcription machinery cooperate to control cell fate decisions and plasticity.

Animals↗