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PubMed2006

Developmental aberrations of liver gene expression in bovine fetuses derived from somatic cell nuclear transplantation.

Cloning by somatic cell nuclear transfer (NT) has been accomplished. However, the process itself is inefficient since most clones die before birth and survivors often display various anomalies. In an effort to determine global expression profiles of developmentally regulated liver genes in NT bovine fetuses, we employed a custom-made bovine liver complementary DNA (cDNA) microarray. The NT fetuses in early pregnancy were derived from cumulus cells as the nuclear donor cells. Normal fetuses were derived from in vitro fertilization (IVF) and artificial insemination (AI). Gene expression levels in NT, IVF, and AI fetal livers were obtained by comparing individual fetal liver samples with that of adult liver of nonpregnant cycling cows. Statistical analyses of the expression data showed widespread dysregulation of developmentally important genes in the three NT fetuses examined. It was found that the number of dysregulated genes was within a range of 3.5-7.7% of the tested genes in the NT fetal livers. The analyses revealed that one NT fetus was markedly different in liver gene expression profile from the other two NT fetal livers in which the expression profiles were highly correlated. Thus, our findings demonstrate that widespread dysregulation of liver genes occurs in the developing liver of NT bovine fetuses. It is possible that inappropriate genomic reprogramming after NT is a key factor associated with abnormal gene expressions in the livers of NT fetuses, whereas distinct expression patterns between the fellow cloned fetuses likely have resulted from variable epigenetic status of the donor nuclei.

Animals↗
PubMed2005

Variable reprogramming of the pluripotent stem cell marker Oct4 in mouse clones: distinct developmental potentials in different culture environments.

A prevailing view of cloning by somatic-cell nuclear transfer is that reprogramming of gene expression occurs during the first few hours after injection of the nucleus into an oocyte, that the process is stochastic, and that the type of reprogramming needed for cloning success is foreign and unlikely to be readily achieved in the ooplasm. Here, we present evidence that the release of reprogramming capacity is contingent on the culture environment of the clone while the contribution of aneuploidy to altered gene expression is marginal. In particular, the rate of blastocyst formation in clones and the regional distribution of mRNA for the pluripotent stem cell marker Oct4 in clonal blastocysts was highly dependent on the culture environment after cumulus cell nuclear transfer, unlike that in genetically equivalent zygotes. Epigenetic modifications of genetically identical somatic nuclei continue after the first cell division of the clones and are amenable to a degree of experimental control, and their development to the blastocyst stage and appropriate expression of Oct4 predict further outcome, such as derivation of embryonic stem (ES) cells, but not fetal development. This observation indicates that development to the blastocyst stage is not equivalent to full reprogramming and lends support to the novel concept that ES cells are not the equivalent of the inner cell mass, hence the discrepancy between ES cell derivability and fetal development of clones.

Animals↗
PubMed2005

The capability of reprogramming the male chromatin after fertilization is dependent on the quality of oocyte maturation.

The present experiments compared the ability of pig oocytes matured either in vivo or in vitro to structurally reorganize the penetrated sperm chromatin into male pronucleus (PN) and to carry out, in parallel, the epigenetic processes of global chromatin methylation and acetylation, 12-14 h after in vitro fertilization (IVF). In addition, PN distribution of histone deacetylase (HDAC), a major enzyme interfacing DNA methylation and histone acetylation, was investigated. The ability of the oocyte to operate an efficient block to polyspermy was markedly affected by maturation. The monospermic fertilization rate was significantly higher for in vivo than for in vitro matured (IVM) oocytes (P < 0.01) which, furthermore, showed a reduced ability to transform the chromatin of penetrated sperm into male PN (P < 0.01). Indirect immunofluorescence analysis of global DNA methylation, histone acetylation and HDAC distribution (HDAC-1, -2 and -3), carried out in monospermic zygotes that reached the late PN stage, showed that IVM oocytes also had a reduced epigenetic competence. In fact, while in about 80% of in vivo matured and IVF oocytes the male PN underwent a process of active demethylation and showed a condition of histone H4 hyperacetylation, only 40% of IVM/IVF zygotes displayed a similar PN remodelling asymmetry. Oocytes that carried out the first part of maturation in vivo (up to germinal vesicle breakdown; GVBD) and then completed the process in vitro, displayed the same PN asymmetry as oocytes matured entirely in vivo. A crucial role of HDAC in the establishment of PN acetylation asymmetry seems to be confirmed by the use of HDAC inhibitors as well as by the abnormal distribution of the enzyme between the two PN in IVM zygotes. Collectively, these data demonstrated that some pig IVM oocytes fail to acquire full remodelling competence which is independent from their ooplasmic ability to morphologically reorganize the sperm nucleus into PN.

Acetylation↗
PubMed2004

Harnessing the developmental potential of nucellar cells: barriers and opportunities.

Angiosperm nucellar cells can either use or avoid meiosis in vivo, depending on the developmental context. This unique ability contrasts with the conditions required in vitro, either for a reconstituted oocyte to avoid meiosis and produce clones by somatic cell nuclear transfer (SCNT), or for mammalian stem cells to undergo meiosis and produce synthetic sex cells (gametes). Current biotechnological initiatives to harness the potential of nucellar cells are based on the transfer of apomixis genes to sexual crop plants with the aim of producing clones through seeds. The elusive genetic basis of apomixis compels us to examine whether this process involves epigenetic factors. The elegant and versatile developmental platform available in nucellar cells should be explored as a genome-scale science and compared with mammalian stem cell biology for a holistic understanding of developmental programming and reprogramming in eukaryotes.

Aspartic Acid Endopeptidases↗
PubMed2003

Epigenetic modifications in an imprinting cluster are controlled by a hierarchy of DMRs suggesting long-range chromatin interactions.

Imprinted genes and their control elements occur in clusters in the mammalian genome and carry epigenetic modifications. Observations from imprinting disorders suggest that epigenetic modifications throughout the clusters could be under regional control. However, neither the elements that are responsible for regional control, nor its developmental timing, particularly whether it occurs in the germline or postzygotically, are known. Here we examine regional control of DNA methylation in the imprinted Igf2-H19 region in the mouse. Paternal germline specific methylation was reprogrammed after fertilization in two differentially methylated regions (DMRs) in Igf2, and was reestablished after implantation. Using a number of knockout strains in the region, we found that the DMRs themselves are involved in regional coordination in a hierarchical fashion. Thus the H19 DMR was needed on the maternal allele to protect the Igf2 DMRs 1 and 2 from methylation, and Igf2 DMR1 was needed to protect DMR2 from methylation. This regional coordination occurred exclusively after fertilization during somatic development, and did not involve linear spreading of DNA methylation, suggesting a model in which long-range chromatin interactions are involved in regional epigenetic coordination. These observations are likely to be relevant to other gene clusters in which epigenetic regulation plays a role, and in pathological situations in which epigenetic regulation is disrupted.

Animals↗
PubMed2004

Histone hypomethylation is an indicator of epigenetic plasticity in quiescent lymphocytes.

Post-translational modifications of histone amino termini are thought to convey epigenetic information that extends the coding potential of DNA. In particular, histone lysine methylation has been implicated in conveying transcriptional memory and maintaining lineage fidelity. Here an analysis of histone lysine methylation in quiescent (G(0)) and cycling lymphocytes showed that methylation of histone H3 at lysines 4 (H3K4), 9 (H3K9), 27 (H3K27) and histone H4 at lysine 20 is markedly reduced in resting B lymphocytes as compared with cycling cells. Quiescent B cells also lacked heterochromatin-associated HP1beta and Ikaros at pericentric chromatin and expressed low levels of Ezh2 and ESET histone methyl transferases (HMTases). Nuclei from resting B or T cells were approximately three times more efficiently reprogrammed in nuclear transfer assays than cells in which HMTase expression, histone methylation and HP1beta binding had been restored following mitotic stimulation. These results showing local and global changes in histone lysine methylation levels in vivo demonstrate that constitutive heterochromatin organization is modified in resting lymphocytes and suggest that histone hypomethylation is a useful indicator of epigenetic plasticity.

Animals↗
PubMed2025

Epitranscriptomic reprogramming in response to low CO2 stress and m6A engineering to enhance biomass production in Nannochloropsis oceanica.

N6-adenine methylation (m6A) as an epitranscriptomic mark is the most abundant modification in eukaryotic RNA and plays a dynamically regulated role. However, m6A dynamics, deposition and engineering in microalgae remain largely unknown. Here, in Nannochloropsis oceanica, the dynamic alterations and reprogramming in m6A RNA modifications after the shift from high to low CO2 conditions were first investigated using methylated RNA immunoprecipitation sequencing. The m6A peaks in N. oceanica were mainly enriched in 3'UTR. A positive association between m6A abundance and mRNA transcription of CO2-responsive genes was observed; moreover, N. oceanica cells adopted versatile strategies in a dynamic reprogramming of m6A in response to low CO2 stress. Secondly, knockout of two putative m6A methylases including NoMTA (NO04G02990) and NoMTB (NO07G02450) by genome editing induced methylation reprogramming, which was associated with expression changes of low-CO2 responsive genes such as carbon/nitrogen metabolism, and photorespiration genes that underlie reductions in growth and biomass. Lastly, m6A modification reprogramming was first engineered to increase low-CO2 stress tolerance and biomass productivity by the CRISPR/dCas13 system combined with MTA and NoMTB under low CO2 in N. oceanica. Therefore, these strides would pave the way for microalgal epigenetics and future industrial applications.

Microalgae↗
PubMed2006

Epigenetic processes and cancer risk assessment.

The U.S. Environmental Protection Agency's Guidelines for Carcinogen Risk Assessment encourages the use of mechanistic data in the assessment of human cancer risk at low (environmental) exposure levels. The key events that define a particular mode of action for tumor formation have been concentrated to date more on mutational responses that are broadly the result of induced DNA damage and enhanced cell proliferation. While it is clear that these processes are important in terms of tumor induction, other modes that fall under the umbrella of epigenetic responses are increasingly being considered to play an important role in susceptibility to tumor induction by environmental chemicals and as significant modifiers of tumor responses. Alterations in gene expression, DNA repair, cell cycle control, genome stability and genome reprogramming could be the result of modification of DNA methylation and chromatin remodeling patterns as a consequence of exposure to environmental chemicals. These concepts are described and discussed.

Animals↗
PubMed2002

Chromatin reprogramming of male somatic cell-derived XIST and TSIX in ES hybrid cells.

In mammalian somatic cells, the X chromosome is active in XY males, whereas one X chromosome is inactivated in XX females. On the active male X chromosome, the XIST and TSIX genes are transcribed in undifferentiated cells of pre-implantation embryos (undifferentiated state) and then down-regulated upon cell differentiation (differentiated state). To explore the epigenetic mechanism involved in the on-off switching of XIST and TSIX transcription in the active X chromosome, male somatic cells were hybridized with male embryonic stem (ES) cells. Fluorescence in situ hybridization analysis revealed that the XIST gene derived from somatic cells was derepressed, as shown by the advent of two pinpoint signals. This was confirmed by strand-specific RT-PCR of XIST and TSIX genes. To analyze changes in chromatin structure in the promoter regions of XIST and TSIX derived from somatic cells, histone tail modifications were studied by chromatin immunoprecipitation analysis. Histones H3 and H4, which were hypoacetylated in the somatic cells, were hyperacetylated in the hybrid cells, and histone H3 lysine 4, which was hypomethylated in the somatic cells, was hypermethylated in the hybrid cells, indicating that the reactivation of XIST and TSIX was linked with chromatin modifications. In the telomeric region of DXPAS34, acetylation of histones H3 and H4 was dependent on reactivation of XIST and TSIX, whereas histone H3 lysine 4 was constitutively methylated independent of the transcriptional activity of those genes. We propose that the chromatin reprogramming is linked with the resetting of the memory found in the process of choosing an active X chromosome.

Animals↗
PubMed2026

HDGF induces inflammatory cancer-associated fibroblast formation through ENO1-mediated glycolytic reprogramming in esophageal squamous-cell carcinoma.

Inflammatory cancer-associated fibroblasts (iCAFs) are a highly plastic stromal population that critically shape tumor progression, immunosuppression, and therapeutic response in esophageal squamous-cell carcinoma (ESCC). Epithelial-intrinsic programs are increasingly recognized as key determinants of fibroblast reprogramming within the tumor microenvironment, yet the underlying mechanisms remain incompletely understood. Here, we identified hepatoma-derived growth factor (HDGF) as a pivotal epithelial-intrinsic regulator that drives iCAF formation in ESCC. Mechanistically, nuclear HDGF functioned as a transcriptional activator by directly binding the ENO1 promoter, thereby upregulating the expression of the glycolytic enzyme enolase 1, enhancing aerobic glycolysis, and promoting lactate secretion from tumor cells. Tumor-derived lactate was subsequently taken up by CAFs and induced histone H4 lysine 12 lactylation (H4K12la), which epigenetically activated NF-&#x3ba;B signaling and promoted iCAF formation. Functionally, HDGF-induced iCAFs promoted tumor progression through activation of the IL-6/JAK1/STAT3 axis and established an immunosuppressive microenvironment characterized by increased recruitment of regulatory T cells and reduced infiltration of CD8+ T cells, thereby facilitating immune evasion. Therapeutically, blockade of ENO1 effectively disrupted the glycolysis-lactylation cascade, markedly suppressing tumor growth and iCAF formation in vivo. Moreover, ENO1 inhibition reprogrammed the immunosuppressive tumor microenvironment and significantly enhanced the efficacy of anti-PD-1 therapy. Collectively, our findings reveal an HDGF/ENO1/H4K12la/iCAF axis that links tumor metabolic reprogramming, stromal inflammatory activation, and immunosuppression in ESCC, identifying this axis as a promising therapeutic target for overcoming immunotherapy resistance.

Phosphopyruvate Hydratase↗
PubMed2005

The theoretical basis of transcriptional therapy of cancer: can it be put into practice?

Aberrant gene silencing is a frequent event in cancer and plays a critical role in the molecular pathogenesis of malignant transformation. The two major mechanisms of silencing in cancer include transcriptional repression by mutated or aberrantly expressed transcription factors, and aberrant epigenetic silencing by hypermethylation of tumor suppressor or DNA repair-related genes. Both of these mechanisms require the activities of multiprotein chromatin remodeling and modifying machines, several of which may be mutated in cancer. The end result is genetic reprogramming of cells to express combinations of genes that confer the neoplastic phenotype. Recent discoveries in transcriptional biochemistry and gene regulation indicate that therapeutic agents can be engineered to specifically target these mechanisms. We provide a framework for the clinical or translational scientist to consider how such drugs might be developed and what their impact might be on restoring cells to normal genetic programming.

Animals↗
PubMed2004

RNAi and HTS: exploring cancer by systematic loss-of-function.

Cancer develops through the successive accumulation and selection of genetic and epigenetic alterations, enabling cells to survive, replicate and evade homeostatic control mechanisms such as apoptosis and antiproliferative signals. This transformation process, however, may create vulnerabilities since the accumulation of mutations can expose synthetic lethal gene interactions and oncogene-driven cellular reprogramming ('addiction'), giving rise to new therapeutic avenues. With the completion of the human genome project, it is anticipated that the identification and characterization of genetic networks that regulate cell growth, differentiation, apoptosis and transformation will be fundamental to decoding the complexity of these processes, and ultimately, cancer itself. Genomic methodologies, such as large-scale mRNA profiling using microarrays, have already begun to reveal the molecular basis of cancer heterogeneity and the clinical behavior of tumors. The combination of traditional cell culture techniques with high-throughput screening approaches has given rise to new cellular-genomics methodologies that enable the simultaneous interrogation of thousands of genes in live cells, facilitating true functional profiling of biological processes. Among these, RNA interference (RNAi) has the potential to enable rapid genome-wide loss-of-function (LOF) screens in mammalian systems, which until recently has been the sole domain of lower organisms. Here, we present a broad overview of this maturing technology and explore how, within current technical constraints, large-scale LOF use of RNAi can be exploited to uncover the molecular basis of cancer--from the genetics of synthetic lethality and oncogene-dependent cellular addiction to the acquisition of cancer-associated cellular phenotypes.

False Negative Reactions↗
PubMed2026

Reframing early gastric carcinogenesis through lineage, niche, and evolution.

Early gastric cancer is still commonly conceptualized as the endpoint of a linear sequence from chronic gastritis to intestinal metaplasia, dysplasia, and invasion. Yet recent single-cell, spatial, genomic, and functional studies indicate that this model incompletely captures the biology of early gastric carcinogenesis. Malignant potential is established progressively within a precancerous gastric field already shaped by somatic evolution, chronic inflammatory injury, and epithelial lineage distortion. Within this field, progression is concentrated in a restricted set of precursor states, particularly incomplete, hybrid, and stem-like metaplastic populations that display plasticity, persistence, and increasing compatibility with a supportive microenvironment. Fibroblast niche remodeling, immune protection loss, endothelial rewiring, genomic instability, epigenetic drift, and selective retention of advantageous molecular alterations further promote malignant commitment. In parallel, diffuse gastric cancer appears to follow a distinct route that may arise independently of conventional intestinal metaplasia through E-cadherin-deficient epithelial transformation and downstream chromatin reprogramming. Here, we synthesize recent evidence to propose an updated framework for early gastric carcinogenesis based on field evolution, lineage instability, ecosystem support, and pathway divergence. Rather than replacing the classical Correa cascade, this framework seeks to refine it by shifting the unit of risk assessment from histologic stage alone to biologically defined precursor states shaped by lineage instability, clonal persistence, niche permissiveness, and pathway-specific molecular constraints. This perspective shifts the emphasis of prevention from detecting smaller cancers to identifying and intercepting biologically committed precursor states before invasion occurs.

Humans↗
PubMed2003

Developmentally regulated usage of Physarum DNA replication origins.

To determine the extent to which eukaryotic replication origins are developmentally regulated in transcriptionally competent cells, we compared origin use in untreated growing amoebae and plasmodia of Physarum polycephalum. At loci that contain genes transcribed in both developmental stages, such as the ribosomal RNA genes and two unlinked actin genes, we show that there is a similar replicational organization, with the same origins used with comparable efficiencies, as shown by two-dimensional agarose-gel electrophoresis. By contrast, we found cell-type-specific replication patterns for the homologous, unlinked profilin A (proA) and profilin P (proP) genes. proA is replicated from a promoter-proximal origin in amoebae, in which it is highly expressed, and is replicated passively in the plasmodium, in which it is not expressed. Conversely, proP is replicated passively and is not expressed in amoebae, but coincides with an efficient origin when highly expressed in the plasmodium. Our results show a reprogramming of S phase that is linked to the reprogramming of transcription during Physarum cell differentiation. This is achieved by the use of two classes of promoter-associated replication origins: those that are constitutively active and those that are developmentally regulated. This suggests that replication origins, like genes, are under epigenetic control associated with cellular differentiation.

Actins↗
PubMed2006

In vivo genomic footprinting using LM-PCR methods.

Epigenetic regulatory proteins such as transcription factors, chromatin components, and chromatin modification activities alter gene activity during development. The means by which alterations in these factors influence gene expression is poorly understood, but information of this kind is essential if we want to reprogram the epigenotype of specific cell types in a directed fashion. To facilitate chromatin structure-function analysis, we have developed a relatively simple procedure that uses magnetic beads to perform ligation-mediated polymerase chain reaction in solid phase. In this chapter, we describe detailed procedures for the examination of chromatin fine-structure and nucleosome positioning as well as changes in transcription factor binding-site occupancy during cellular differentiation.

Animals↗
PubMed2007

The commonality of plasticity underlying multipotent tumor cells and embryonic stem cells.

Aggressive cancer cells and pluripotent stem cells converge in their capacity for self-renewal, proliferation and plasticity. Recent studies have capitalized on these similarities by demonstrating that tumors arise from specific cancer stem cell populations that, in a manner reminiscent of normal stem cells, are able to both self-renew and give rise to a heterogeneous tumor population. This stem cell like function of aggressive cancer cells is likely attributable to the ectopic expression of embryonic factors such as Nodal and Cancer Testis Specific Antigens (CTAs), which maintain a functional plasticity by promoting pluripotency and immortality. During development, the expression of these embryonic factors is tightly regulated by a dynamic array of mediators, including the spatial and temporal expression of inhibitors such as Lefty, and the epigenetic modulation of the genome. In aggressive cancer cells, particularly melanoma, this balance of regulatory mediators is disrupted, leading to the aberrant expression of pluripotency-associated genes. By exposing aggressive cancer cells to embryonic microenvironments, this balance of regulatory mediators is restored, thereby reprogramming tumor cells to a more benign phenotype. These stem cell-derived mediators, as well as the genes they regulate, provide therapeutic targets designed to specifically differentiate and eradicate aggressive cancers.

Cell Lineage↗
PubMed2003

[Epigenetic modifications and its impact on animal cloning].

Despite recent successes in cloning various mammals and amphibians, the low efficiency of animals production and abnormal symptoms in many cloned animals are crucial problems in cloning technology. To overcome these problems, scientists focus on mechanisms of cloning. A possible cause of the low success frequency of cloning is the insufficient dedifferentiation and the inadequate reprogramming of the high differentiated adult somatic nucleus in enucleated oocytes, which caused by incomplete methylation and premature de novo remethylation of donor DNA. In cloned embryos the methylation level is higher than normal embryos, and this may cause aberrant expression of several important genes, especially imprinting genes. Study on these mechanisms is very important to improve the rate of successful cloned animals.

Animals↗
PubMed2026

Ovarian aging and systemic health: Mechanisms and emerging intervention strategies.

Ovarian aging may contribute to systemic aging via the ovarian-systemic axis. This review outlines intrinsic ovarian cellular defects such as genomic instability, epigenetic shifts, and mitochondrial and proteostasis damage, which may trigger senescence-associated secretory phenotype (SASP)-related inflammaging, fibrosis, and distal pro-aging signals. Ovarian-derived endocrine disruption, especially estrogen decline, broadly affects bodily physiology. We summarize emerging multimodal interventions, including senolytics, metabolic reprogramming, regenerative medicine, and systemic approaches, and we discuss their dual potential to preserve fertility and intercept ovarian contributions to systemic aging. Ovarian aging is possibly associated with female age-related multimorbidity. Ovary-targeted prevention may extend healthspan, as assessed by combined reproductive and systemic clinical evaluations.

Humans↗