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PubMed2025

Exogenous BMI1 expression aggravates oral squamous cell carcinomas in tongue epithelia.

Oral squamous cell carcinoma (OSCC) is characterized by aggressiveness and a poor prognosis, in part because most patients are diagnosed during the later stages of the disease. B cell-specific Moloney murine leukemia virus integration site 1 (BMI1), part of polycomb repressive complex 1 (PRC1), is a key transcription factor overexpressed in OSCC. Although increased BMI1 has been linked to tumor formation in mouse models of the disease, the molecular mechanisms have not been elucidated. Here we used a transgenic mouse line (KrTB) that selectively overexpresses BMI1 in the tongue basal epithelial stem cells (SCs) to delineate BMI1 actions during oral tumorigenesis. By tumor pathological classification after 4-nitroquinoline 1-oxide (4-NQO)-induced carcinogenesis we detected more severe tumors in mice with ectopic BMI1 expression. Genome-wide transcriptomics indicated that mRNAs associated with human OSCC, including SOX9, HIF1A, MMP9, INHBB, and MYOF, were further increased by ectopic BMI1 expression in murine tongue epithelia. mRNAs encoding multiple metabolic targets, such as SLC2A1 (GLUT1), PKM, LDHA, and HK2, were also increased upon BMI1 overexpression in 4-NQO-treated tongue epithelia. Furthermore, we detected BMI1, SOX9, and GLUT1 proteins in the infiltrating cells of invasion fronts identified by markers of invasive SCCs. Finally, metabolomic data show that BMI1 overexpression in tongue epithelia promotes glycolysis during 4-NQO-induced carcinogenesis. Thus, our data demonstrate that BMI1 causes OSCC cells to alter cell metabolism, as changes in many of these transcripts are linked to increased glycolysis and metabolic reprograming that occurs during carcinogenesis.

Animals↗
PubMed2004

Identification of potential nuclear reprogramming and differentiation factors by a novel selection method for cloning chromatin-binding proteins.

Nuclear reprogramming is critical for animal cloning and stem cell creation through nuclear transfer, which requires extensive remodeling of chromosomal architecture involving dramatic changes in chromatin-binding proteins. To understand the mechanism of nuclear reprogramming, it is critical to identify chromatin-binding factors specify the reprogramming process. In this report, we have developed a high-throughput selection method, based on T7 phage display and chromatin immunoprecipitation, to isolate chromatin-binding factors expressed in mouse embryonic stem cells using primary mouse embryonic fibroblast chromatin. Seven chromatin-binding proteins have been isolated by this method. We have also isolated several chromatin-binding proteins involved in hepatocyte differentiation. Our method provides a powerful tool to rapidly and selectively identify chromatin-binding proteins. The method can be used to study epigenetic modification of chromatin during nuclear reprogramming, cell differentiation, and transdifferentiation.

Animals↗
PubMed1997

Nuclear transfer and reprogramming.

Nuclear transfer techniques for mammalian embryos have been developed in the last decade. Embryonic nuclei from advanced stages of preimplantation development can be fully reprogrammed and the totipotency is restored when nuclei are transferred into ooplasts. Transfer of nuclei after gene expression from the embryonic genome has started does not appear to restrict the reprogramming of these nuclei. The principles of nuclear transfer are outlined with respect to nuclear remodelling, nucleocytoplasmic interactions and effects of the cell cycle. However, the molecular mechanisms involved in reprogramming donor nuclei remain unknown. It is proposed that epigenetic DNA modification, such as DNA methylation that regulates gene expression, is related to the reprogramming of transplanted nuclei.

Animals↗
PubMed2004

Genetic and epigenetic aspects of cloning and potential effects on offspring of cloned mammals.

Although the biological mechanisms by which host cytoplasm and donor nuclei interact to produce a developmentally competent reconstructed embryo remain largely unknown, some advances have been made to our understanding of the genetic and epigenetic factors involved in the of reprogramming of the donor nucleus. Genetic alterations, which comprise changes to the genetic information in both the nuclear and cytoplasm compartments, are passed on to subsequent generations at fertilization and are a potential source of variation among cloned animals and their offspring. Apart from the major chromosomal anomalies found in developmentally arrested embryos and fetuses, less detrimental rearrangements and/or mutations are likely to go unnoticed in most donor cell karyotypes, suggesting that such problems could lead to inheritable anomalies among clones and their offspring. Mitochondrial DNA is also relevant to cloning because most animals inherit most or all of their mitochondria from the host oocyte. Epigenetic alterations to the DNA or to the histone packaging proteins are independent of gene sequences. Aberrant epigenetic events may lead to variable gene expression or mitosis and consequent effects on development and phenotype. Although much of the epigenetic marking is reset during embryogenesis and development, the impact of epimutations on progeny remains unexplored.

Animals↗
PubMed2006

CAF-1 is essential for heterochromatin organization in pluripotent embryonic cells.

During mammalian development, chromatin dynamics and epigenetic marking are important for genome reprogramming. Recent data suggest an important role for the chromatin assembly machinery in this process. To analyze the role of chromatin assembly factor 1 (CAF-1) during pre-implantation development, we generated a mouse line carrying a targeted mutation in the gene encoding its large subunit, p150CAF-1. Loss of p150CAF-1 in homozygous mutants leads to developmental arrest at the 16-cell stage. Absence of p150CAF-1 in these embryos results in severe alterations in the nuclear organization of constitutive heterochromatin. We provide evidence that in wild-type embryos, heterochromatin domains are extensively reorganized between the two-cell and blastocyst stages. In p150CAF-1 mutant 16-cell stage embryos, the altered organization of heterochromatin displays similarities to the structure of heterochromatin in two- to four-cell stage wild-type embryos, suggesting that CAF-1 is required for the maturation of heterochromatin during preimplantation development. In embryonic stem cells, depletion of p150CAF-1 using RNA interference results in the mislocalization, loss of clustering, and decondensation of pericentric heterochromatin domains. Furthermore, loss of CAF-1 in these cells results in the alteration of epigenetic histone methylation marks at the level of pericentric heterochromatin. These alterations of heterochromatin are not found in p150CAF-1-depleted mouse embryonic fibroblasts, which are cells that are already lineage committed, suggesting that CAF-1 is specifically required for heterochromatin organization in pluripotent embryonic cells. Our findings underline the role of the chromatin assembly machinery in controlling the spatial organization and epigenetic marking of the genome in early embryos and embryonic stem cells.

Animals↗
PubMed1986

Nuclear transplantation in the mouse: heritable differences between parental genomes after activation of the embryonic genome.

Paternal and maternal genomes apparently have complementary roles during embryogenesis in the mouse, and both are essential for development to term. However, there is no direct evidence to show that functional differences between parental genomes remain intact after activation of the embryonic genome at the 2-cell stage. In this study we demonstrate that transfer of paternal or maternal nuclei from early haploid preimplantation embryos back to fertilized eggs from which one pronucleus was removed resulted in development to term, but only if the remaining pronucleus was of the parental type opposite to the donor nucleus. Hence, functional differences between parental chromosomes are heritable and they survive activation of the embryonic genome and probable reprogramming of donor embryonic nuclei by epigenetic factors in the egg cytoplasm.

Animals↗
PubMed2006

Active cytosine demethylation triggered by a nuclear receptor involves DNA strand breaks.

Cytosine methylation at CpG dinucleotides contributes to the epigenetic maintenance of gene silencing. Dynamic reprogramming of DNA methylation patterns is believed to play a key role during development and differentiation in vertebrates. The mechanisms of DNA demethylation remain unclear and controversial. Here, we present a detailed characterization of the demethylation of an endogenous gene in cultured cells. This demethylation is triggered in a regulatory region by a transcriptional activator, the glucocorticoid receptor. We show that DNA demethylation is an active process, occurring independently of DNA replication, and in a distributive manner without concerted demethylation of cytosines on both strands. We demonstrate that the DNA backbone is cleaved 3' to the methyl cytidine during demethylation, and we suggest that a DNA repair pathway may therefore be involved in this demethylation.

Animals↗
PubMed2003

Cloned cattle fetuses with the same nuclear genetics are more variable than contemporary half-siblings resulting from artificial insemination and exhibit fetal and placental growth deregulation even in the first trimester.

The cloning of cattle by somatic cell nuclear transfer (NT) is associated with a high incidence of abnormal placentation, excessive fluid accumulation in the fetal sacs (hydrops syndrome), and fetal overgrowth. Fetal and placental development was investigated at Day 50, during placentome formation; at Day 100, when placentation was completed; and at Day 150, when the hydrops syndrome frequently develops. The NT fetuses were compared with contemporary half-siblings generated from in vitro-produced embryos or by artificial insemination (AI). Fetal cotyledon formation and vascularization of the chorioallantoic membranes was initiated normally in NT conceptuses, but fewer cotyledons successfully formed placentomes. By Day 100, the mean number of placentomes was significantly lower in surviving NT fetuses. Only those with normal placentome numbers were represented in surviving NT pregnancies at Day 150. The mean total caruncle tissue weight of the placentomes was significantly higher in the surviving NT groups at Days 100 and 150, irrespective of the placentome numbers, indicating that increased NT placental weight was caused by excessive uterine tissue growth. By Day 100, NT fetuses exhibited growth deregulation, and those that survived to Day 150 were 17% heavier than contemporary AI controls. Placentome, liver, and kidney overgrowth accompanied the hydrops syndrome at Day 150. The NT fetal overgrowth was not a consequence of in vitro embryo culture and showed no correlation with placental overgrowth. However, in vitro culture and incomplete reprogramming of the donor genome are epigenetic effects that may override genetic traits and contribute to the greater variability in placental and fetal development in the NT group compared with AI half-siblings.

Amniotic Fluid↗
PubMed2005

Imprinted X inactivation and reprogramming in the preimplantation mouse embryo.

X chromosome inactivation is a developmentally regulated process that causes one of the two X chromosomes in normal female mammals to become transcriptionally silenced, thus equalizing the expression of X-linked genes between the sexes. Such dosage compensation depends upon dynamic genetic and epigenetic events occurring very early in development. X inactivation is controlled by an X inactivation centre that is associated with the expression of non-coding RNAs required for the silencing. Also associated with the inactive X are repressive histone modifications and polycomb protein-mediated states, which are progressively acquired during the inactivation process. In mouse, two forms of X inactivation have been described. Random X inactivation happens in the derivatives of the inner cell mass (ICM) giving rise to embryos where the maternally inherited X(Xm) is inactive in some cells and the paternally derived X (Xp) is inactive in others. Random X inactivation occurs around the time of implantation. Imprinted X inactivation, the preferential inactivation of the Xp chromosome, occurs earlier and, although there has been some debate as to the precise timing of initiation of this event, is apparent in all cells early in preimplantation development, then is subsequently confined to the cells of the extraembryonic lineages. A picture is emerging whereby initial epigenetic asymmetry between the two parental X chromosomes is reprogrammed in a lineage specific manner resulting in a switch from imprinted to random inactivation in embryonic derivatives. Neither the underlying reason nor the full extent of these early lineage specific epigenetic changes is known, but they may be correlated with more genome-wide reprogramming events essential for normal development.

Alleles↗
PubMed2003

[Nuclear transfer and reprogramming mechanism].

It is confident that mammalian somatic cell and embryonic stem cell can form whole individuals if they are transferred to enucleated oocytes at M phase. However, a large proportion of clones were stillborn or died within several months due to various reasons. Morphological abnormalities have also been observed in clones. The exact reasons for such abnormalities are not clear, but genetic or epigenetic modification in donor cells and insufficient reprogramming of nuclei due to improper nuclear transfer technique are considered. In this review, we discuss the present status of animal cloning and reprogramming mechanism of nuclei.

Animals↗
PubMed2006

Chromatin decondensation and nuclear reprogramming by nucleoplasmin.

Somatic cell nuclear cloning has repeatedly demonstrated striking reversibility of epigenetic regulation of cell differentiation. Upon injection into eggs, the donor nuclei exhibit global chromatin decondensation, which might contribute to reprogramming the nuclei by derepressing dormant genes. Decondensation of sperm chromatin in eggs is explained by the replacement of sperm-specific histone variants with egg-type histones by the egg protein nucleoplasmin (Npm). However, little is known about the mechanisms of chromatin decondensation in somatic nuclei that do not contain condensation-specific histone variants. Here we found that Npm could widely decondense chromatin in undifferentiated mouse cells without overt histone exchanges but with specific epigenetic modifications that are relevant to open chromatin structure. These modifications included nucleus-wide multiple histone H3 phosphorylation, acetylation of Lys 14 in histone H3, and release of heterochromatin proteins HP1beta and TIF1beta from the nuclei. The protein kinase inhibitor staurosporine inhibited chromatin decondensation and these epigenetic modifications with the exception of H3 acetylation, potentially linking these chromatin events. At the functional level, Npm pretreatment of mouse nuclei facilitated activation of four oocyte-specific genes from the nuclei injected into Xenopus laevis oocytes. Future molecular elucidation of chromatin decondensation by Npm will significantly contribute to our understanding of the plasticity of cell differentiation.

Animals↗
PubMed1990

DNA methylation and epigenetic inheritance.

Classical genetics has revealed the mechanisms for the transmission of genes from generation to generation, but the strategy of the genes in unfolding the developmental programme remains obscure. Epigenetics comprises the study of the mechanisms that impart temporal and spatial control on the activities of all those genes required for the development of a complex organism from the zygote to the adult. Epigenetic changes in gene activity can be studied in relation to DNA methylation in cultured mammalian cells and it is also possible to isolate and characterize mutants with altered DNA methylase activity. Although this experimental system is quite far removed from the epigenetic controls acting during development it does provide the means to clarify the rules governing the silencing of genes by specific DNA methylation and their reactivation by demethylation. This in turn will facilitate studies on the control of gene expression in somatic cells of the developing organism or the adult. The general principles of epigenetic mechanisms can be defined. There are extreme contrasts between instability or switches in gene expression, such as those in stem-line cells, and the stable heritability of a specialized pattern of gene activities. In some situations cell lineages are known to be important, whereas in others coordinated changes in groups of cells have been demonstrated. Control of numbers of cell divisions and the size of organisms, or parts of organisms, is also essential. The epigenetic determination of gene expression can be reversed or reprogrammed in the germ line. The extent to which methylation or demethylation of specific DNA sequences can help explain these basic epigenetic mechanisms is briefly reviewed.

Aging↗
PubMed2006

Reprogramming efficiency following somatic cell nuclear transfer is influenced by the differentiation and methylation state of the donor nucleus.

Reprogramming of a differentiated cell nucleus by somatic cell nuclear transplantation is an inefficient process. Following nuclear transfer, the donor nucleus often fails to express early embryonic genes and establish a normal embryonic pattern of chromatin modifications. These defects correlate with the low number of cloned embryos able to produce embryonic stem cells or develop into adult animals. Here, we show that the differentiation and methylation state of the donor cell influence the efficiency of genomic reprogramming. First, neural stem cells, when used as donors for nuclear transplantation, produce embryonic stem cells at a higher efficiency than blastocysts derived from terminally differentiated neuronal donor cells, demonstrating a correlation between the state of differentiation and cloning efficiency. Second, using a hypomorphic allele of DNA methyltransferase-1, we found that global hypomethylation of a differentiated cell genome improved cloning efficiency. Our results provide functional evidence that the differentiation and epigenetic state of the donor nucleus influences reprogramming efficiency.

Animals↗
PubMed2025

Setdb2 Regulates Inflammatory Trigger-Induced Trained Immunity of Macrophages Through Two Different Epigenetic Mechanisms.

"Trained immunity" of innate immune cells occurs through a sequential two-step process where an initial pathogenic or sterile inflammatory trigger is followed by an amplified response to a later un-related secondary pathogen challenge. The memory effect is mediated at least in part through epigenetic modifications of the chromatin landscape. Here, we investigated the role of the epigenetic modifier Setdb2 in microbial (β-glucan) or sterile trigger (Western-diet-WD/oxidized-LDL-oxLDL)-induced trained immunity of macrophages. Using genetic mouse models and genomic analysis, we uncovered a critical role of Setdb2 in regulating proinflammatory and metabolic pathway reprogramming. We further show that Setdb2 regulates trained immunity through two different complementary mechanisms: one where it positively regulates glycolytic and inflammatory pathway genes via enhancer-promoter looping, and is independent of its enzymatic activity; while the second mechanism is associated with both increased promoter associated H3K9 methylation and repression of interferon response pathway genes. Interestingly, while both mechanisms occur in response to pathogenic training, only the chromatin-looping mechanism operates in response to the sterile inflammatory stimulus. These results reveal a previously unknown bifurcation in the downstream pathways that distinguishes between pathogenic and sterile inflammatory signaling responses associated with the innate immune memory response and may provide potential therapeutic opportunities to target cytokine vs. interferon pathways to limit complications of chronic inflammation.

Setdb2↗
PubMed2006

Erasure of methylation imprint at the promoter and CTCF-binding site upstream of H19 in human testicular germ cell tumors of adolescents indicate their fetal germ cell origin.

Genome-wide epigenetic modification plays a crucial role in regulating genome functions at critical stages of development. In particular, DNA methylation is known to be reprogrammed on a genome-wide level in germ cells and in preimplantation embryos, although it is relatively stable in somatic cells. In this reprogramming process, the genome becomes demethylated, and methylated de novo during later stages of development. Reprogramming of DNA methylation in male germ cells has not been fully investigated. Testicular germ cell tumors (TGCTs) possess a pluripotential nature and display protean histology from germ cells to embryonal and somatic cell differentiation. These properties make TGCT a unique model for studying germ cell development and gametogenesis in respect of DNA reprogramming. In order to obtain an insight into the epigenetic dynamics of TGCTs, we conducted a comprehensive analysis of differential methylated regions (DMRs) on H19 and IGF2 in TGCTs compared with testicular malignant lymphomas. In the present study, we show that methylation imprint at the promoter and CTCF-binding site upstream of H19 was completely erased in both seiminomatous and non-seminomatous TGCTs, whereas differential methylation was observed in testicular lymphomas. The erasure of methylation imprint was also observed in TGCTs with malignant transformation. We found biallelic unmethylation at the promoter and the CTCF-binding site upstream of H19 is required, but not sufficient for the biallelic expression of H19 in TGCTs. These data suggest that factors other than methylation contribute to transcriptional regulation of imprinted genes in TGCTs. The present data have shown that TGCTs carry distinctive epigenetic profiles at the core-imprinting domain of H19/IGF2 from other neoplasms of somatic cell origin. The data also suggest that both seminomatous and non-seminomatous TGCTs carry methylation profiles similar to fetal germ cells, but not adult germ cells, indicating the origin of TGCTs as fetal germ cells.

Adolescent↗
PubMed2003

Reprogramming in nuclear transfer.

Reprogramming a nucleus by transferring it to oocyte cytoplasm triggers epigenetic changes that eventually lead to the restoration of a totipotent state and the birth of a viable animal. A simplified way of studying this complex process is to study cell hybrids. These studies suggest that the pluripotent character of one nucleus is dominant over that of the other nucleus. The development of nuclear transfer embryos shows that there are several restriction points and that the extra-embryonic lineages may be the primary source of death. Successful reprogramming depends on the balance between epigenetic modifications and the regulative properties of development.

Animals↗
PubMed2002

Mammalian embryonic development--insights from studies on the X chromosome.

This paper reviews our early studies on the cycle of changes of X chromosome activity in different lineages of the developing female mouse embryo. The emphasis is placed on the insights gained into key developmental processes such as the temporal and spatial aspects of developmental totipotency, the timing and cell numbers involved in the origin of the germ line, the molecular mechanisms of genetic deprogramming, reprogramming and X chromosome imprinting, and transgenerational epigenetic inheritance. When viewed in this way, it is quite remarkable to see how much was learned about mammalian development from early studies on the X chromosome. Indeed several paradigm shifts occurred as a result of these studies and these are highlighted in this review.

Animals↗
PubMed2006

Nuclear reprogramming: an overview.

Nuclear reprogramming is an intriguing phenomenon, in which specialized somatic cells reacquire pluripotency through the global resetting of epigenetic modifications without changes occurring to their nuclear DNA information. The nuclear reprogramming activity retained by unfertilized eggs and embryonic stem cells is readily observable through the techniques of nuclear transplantation and cell fusion, respectively. Furthermore, researches involving somatic stem cells have provided evidence that spontaneous cell fusion functions, at least in part, in maintaining the homeostasis of various tissues through the generation of replacement cells in vivo. Novel approaches by application of the nuclear reprogramming activity may open new avenues producing genetically matched personalized pluripotential stem cells derived from patient somatic cells.

Animals↗