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PubMed2002

Epigenetic risks related to assisted reproductive technologies: risk analysis and epigenetic inheritance.

A broad spectrum of assisted reproductive technologies has become available for couples with fertility problems. Follow-up studies of children born as a result of assisted reproduction have shown that neonatal outcome and malformation rates are not different from those of the general population, except for a low birthweight and a slight increase in chromosomal abnormalities. The safety aspect of assisted reproduction at the epigenetic level has not been well studied. Epigenetics refers to phenomena where modifications of DNA methylation and/or chromatin structure underlie changes in gene expression and phenotype characteristics. This article intends to analyse epigenetic risks related to assisted reproduction on the basis of an overview of epigenetic reprogramming events in the gamete and early embryo. Two epigenetic modifications, methylation and imprinting, are considered in more detail. The interference of in-vitro embryo culture, immature sperm cells and nuclear transfer with epigenetic reprogramming is discussed, as well as the possibility of epigenetic inheritance.

Animals↗
PubMed1998

Histone deacetylase homologs regulate epigenetic inheritance of transcriptional silencing and chromosome segregation in fission yeast.

Position-effect control at the silent mat2-mat3 interval and at centromeres and telomeres in fission yeast is suggested to be mediated through the assembly of heterochromatin-like structures. Therefore, trans-acting genes that affect silencing may encode either chromatin proteins, factors that modify them, or factors that affect chromatin assembly. Here, we report the identification of an essential gene, clr6 (cryptic loci regulator), which encodes a putative histone deacetylase that when mutated affects epigenetically maintained repression at the mat2-mat3 region and at centromeres and reduces the fidelity of chromosome segregation. Furthermore, we show that the Clr3 protein, when mutated, alleviates recombination block at mat region as well as silencing at donor loci and at centromeres and telomeres, also shares strong homology to known histone deacetylases. Genetic analyses indicate that silencing might be regulated by at least two overlapping histone deacetylase activities. We also found that transient inhibition of histone deacetylase activity by trichostatin A results in the increased missegregation of chromosomes in subsequent generations and, remarkably, alters the imprint at the mat locus, causing the heritable conversion of the repressed epigenetic state to the expressed state. This work supports the model that the level of histone deacetylation has a role in the assembly of repressive heterochromatin and provides insight into the mechanism of epigenetic inheritance.

Amino Acid Sequence↗
PubMed2004

Epigenetic inheritance of fetal genes in allergic asthma.

Asthma has been associated with an exaggerated T-helper type 2 (Th2) over Th1 responses to allergic and nonallergic stimuli, which leads to chronic airway inflammation and airway remodeling. In the present article, we propose that many of the genes involved in IgE synthesis and airways (re)modeling in asthma are persistent or reminiscent fetal genes which may not be silenced during early infancy (or late pregnancy). Genes of the embryologic differentiation of ectodermic and endodermic tissues may explain some of the patterns of airway remodeling in asthma. In utero programming leads to gene expression, the persistence of which may be associated with epigenetic inheritance phenomena induced by nonspecific environmental factors. Clear delineation of these issues may yield new information on the mechanisms of asthma and new targets for therapeutic intervention and primary prevention.

Asthma↗
PubMed2006

Parental obesity and overweight affect the body-fat accumulation in the offspring: the possible effect of a high-fat diet through epigenetic inheritance.

The prevalence of obesity in adults has been rising continually, as has the prevalence of childhood obesity, and a large number of epidemiological studies have demonstrated a direct relationship between parental obesity and childhood obesity. In this paper, we review the effect of diet, the intrauterine environment, and the genetic inheritance on obesity. We described a study in detail that used experimental animals as a model to investigate the effect of a parental high-fat diet on body-fat accumulation in their offspring. Fertilized eggs were transplanted in that study, and body-fat accumulation in the offspring of the parents fed a high-fat diet was found to be greater than in the offspring of the parents fed a low-fat diet, even when the experimental conditions were the same in the intrauterine and subsequent environment. The results suggested that a parental high-fat diet before intrauterine developmental stage may increase body-fat accumulation in the offspring. We discuss the possibility that parental diet may influence the lifelong health of offspring and epigenetic inheritance may be occurred.

Adult Children↗
PubMed1997

Epigenetic inheritance of transcriptional silencing and switching competence in fission yeast.

Epigenetic events allow the inheritance of phenotypic changes that are not caused by an alteration in DNA sequence. Here we characterize an epigenetic phenomenon occurring in the mating-type region of fission yeast. Cells of fission yeast switch between the P and M mating-type by interconverting their expressed mating-type cassette between two allelic forms, mat1-P and mat1-M. The switch results from gene conversions of mat1 by two silent cassettes, mat2-P and mat3-M, which are linked to each other and to mat1. GREWAL and KLAR observed that the ability to both switch mat1 and repress transcription near mat2-P and mat3-M was maintained epigenetically in a strain with an 8-kb deletion between mat2 and mat3. Using a strain very similar to theirs, we determined that interconversions between the switching- and silencing-proficient state and the switching and silencing-deficient state occurred less frequently than once per 1000 cell divisions. Although transcriptional silencing was alleviated by the 8-kb deletion, it was not abolished. We performed a mutant search and obtained a class of trans-acting mutations that displayed a strong cumulative effect with the 8-kb deletion. These mutations allow to assess the extent to which silencing is affected by the deletion and provide new insights on the redundancy of the silencing mechanism.

Alleles↗
PubMed2002

Changes in the middle region of Sup35 profoundly alter the nature of epigenetic inheritance for the yeast prion [PSI+].

The yeast prion [PSI(+)] provides an epigenetic mechanism for the inheritance of new phenotypes through self-perpetuating changes in protein conformation. [PSI(+)] is a nonfunctional, ordered aggregate of the translation termination factor Sup35p that influences new Sup35 proteins to adopt the same state. The N-terminal region of Sup35p plays a central role in prion induction and propagation. The C-terminal region provides translation termination activity. The function of the highly charged, conformationally flexible middle region (M) is unknown. An M deletion mutant was capable of existing in either the prion or the nonprion state, but in either case it was mostly insoluble. Substituting a charged synthetic polypeptide for M restored solubility, but the prions formed by this variant were mitotically very unstable. Substituting charged flexible regions from two other proteins for M created variants that acquired prion states (defined as self-perpetuating changes in function transferred to them from wild-type [PSI(+)] elements), but had profoundly different properties. One was soluble in both the prion and the nonprion form, mitotically stable but meiotically unstable, and cured by guanidine HCl but not by alterations in heat shock protein 104 (Hsp104p). The other could only maintain the prion state in the presence of wild-type protein, producing Mendelian segregation patterns. The unique character of these M variants, all carrying the same N-terminal prion-determining region, demonstrate the importance of M for [PSI(+)] and suggest that a much wider range of epigenetic phenomena might be based on self-perpetuating, prion-like changes in protein conformation than suggested by our current methods for defining prion states.

Base Sequence↗
PubMed2000

PCNA connects DNA replication to epigenetic inheritance in yeast.

Formation of a heterochromatin-like structure results in transcriptional silencing at the HM mating-type loci and telomeres in Saccharomyces cerevisiae. Once formed, such epigenetically determined structures are inherited for many mitotic divisions. Here we show that mutations in the proliferating cell nuclear antigen (PCNA), an essential component at the DNA replication fork, reduced repression of genes near a telomere and at the silent mating-typelocus, HMR. The pol30-8 mutant displayed coexistence of both repressed (pink) and de-repressed (white) cells within a single colony when assayed with the ADE2 gene inserted at HMR. Unlike pol30-8, the pol30-6 and pol30-79 mutants partially reduced gene silencing at telomeres and the HMR and synergistically decreased silencing in cells lacking chromatin assembly factor 1 (CAF-1). All silencing defective mutants showed reduced binding to CAF-1 in vitro and altered chromatin association of the CAF-1 large subunit in vivo. Thus, PCNA participates in inheritance of both DNA and epigenetic chromatin structures during the S phase of the cell cycle, the latter by at least two mechanisms.

Carboxy-Lyases↗
PubMed2004

Reprogramming of epigenetic inheritance by somatic cell nuclear transfer.

Somatic cloning by nuclear transfer returns a differentiated cell to a totipotent stage, a process termed nuclear reprogramming. During this de-differentiation process, genes inactivated during tissue differentiation are re-activated in a temporal and spatial special manner. It is believed that tissue differentiation occurs through epigenetic mechanisms, genetic inheritance that does not involve changes in DNA sequences. Developmental abnormalities and a high mortality rate in cloned offspring have frequently been observed and probably result from incomplete nuclear reprogramming. In this review, the reprogramming of two epigenetic mechanisms, imprinting and X chromosome inactivation, as well as recent attempts to modify pre-existing epigenetic marks in donor cells to improve nuclear transfer efficacy, are discussed.

Animals↗
PubMed2004

Noncompetitive counteractions of DNA polymerase epsilon and ISW2/yCHRAC for epigenetic inheritance of telomere position effect in Saccharomyces cerevisiae.

Relocation of euchromatic genes near the heterochromatin region often results in mosaic gene silencing. In Saccharomyces cerevisiae, cells with the genes inserted at telomeric heterochromatin-like regions show a phenotypic variegation known as the telomere-position effect, and the epigenetic states are stably passed on to following generations. Here we show that the epigenetic states of the telomere gene are not stably inherited in cells either bearing a mutation in a catalytic subunit (Pol2) of replicative DNA polymerase epsilon (Pol epsilon) or lacking one of the nonessential and histone fold motif-containing subunits of Pol epsilon, Dpb3 and Dpb4. We also report a novel and putative chromatin-remodeling complex, ISW2/yCHRAC, that contains Isw2, Itc1, Dpb3-like subunit (Dls1), and Dpb4. Using the single-cell method developed in this study, we demonstrate that without Pol epsilon and ISW2/yCHRAC, the epigenetic states of the telomere are frequently switched. Furthermore, we reveal that Pol epsilon and ISW2/yCHRAC function independently: Pol epsilon operates for the stable inheritance of a silent state, while ISW2/yCHRAC works for that of an expressed state. We therefore propose that inheritance of specific epigenetic states of a telomere requires at least two counteracting regulators.

Adenosine Triphosphatases↗
PubMed1994

Genomic imprinting: control of gene expression by epigenetic inheritance.

One parental copy of an imprinted gene is invariably expressed during development. The characteristic of the heritable epigenetic germline imprint remains elusive, but recent evidence stresses the necessity for additional post-zygotic epigenetic modifications to account for this temporal and tissue-specific mono-allelic expression. Preliminary insight into a diversity of post-zygotic control mechanisms is beginning to emerge.

Animals↗
PubMed2002

DNA methylation and epigenetic inheritance.

Mammalian cell lines silence genes at low frequency by the methylation of promoter sequences. These silent genes can be reactivated at high frequency by the demethylating agent 5-azacytidine (5-aza-CR). The inactive and active epigenetic states of such genes are stably inherited. A method for silencing genes is now available. It involves treatment of permeabilized cells with 5-methyl deoxycytidine triphosphate (5-methyl dCTP) which is incorporated into DNA. The methylation of promoter sequences has been confirmed using the bisulfite genomic sequencing procedure. Methylated oligonucleotides homologous to promoter sequences might be used to specifically target and silence given genes, but results so far have not been conclusive. Treatments that silence or reactivate genes by changing DNA methylation can be referred to as epimutagens, as distinct from mutagens that act by changing DNA sequences. The epimutagen 5-aza-CR reactivates genes but has little mutagenic activity, whereas standard mutagens (such as ethyl methane sulfonate and ultraviolet light) have little reactivation activity. Nevertheless, much more information is required about the effects of DNA-damaging agents in changing DNA methylation and gene activity and also about the role of epimutations in tumor progression.

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↗
PubMed1998

The Drosophila Fab-7 chromosomal element conveys epigenetic inheritance during mitosis and meiosis.

Polycomb group (PcG) and trithorax group (trxG) gene products are responsible for the maintenance of repressed and active expression patterns of many developmentally important regulatory genes including the homeotic genes. In Drosophila embryos, Polycomb protein and the trxG protein GAGA factor colocalize at the Fab-7 DNA element of the bithorax complex. In transgenic lines, the Fab-7 element induces extensive silencing on a flanking GAL4-driven lacZ reporter and mini-white genes. However, a short single pulse of GAL4 during embryogenesis is sufficient to release PcG-dependent silencing from the transgene. Such an activated state of Fab-7 is mitotically inheritable through development and can be transmitted in a GAL4-independent manner to the subsequent generations through female meiosis. Thus, Fab-7 is a switchable chromosomal element, which can convey memory of epigenetically determined active and repressed chromatin states.

ATP-Binding Cassette Transporters↗
PubMed2001

DNA methylation and epigenetic inheritance in plants and filamentous fungi.

Plants and filamentous fungi share with mammals enzymes responsible for DNA methylation. In these organisms, DNA methylation is associated with gene silencing and transposon control. However, plants and fungi differ from mammals in the genomic distribution, sequence specificity, and heritability of methylation. We consider the role that transposons play in establishing methylation patterns and the epigenetic consequences of their perturbation.

DNA Methylation↗
PubMed1999

Epigenetic inheritance of active chromatin after removal of the main transactivator.

The Drosophila Polycomb and trithorax group proteins act through chromosomal elements such as Fab-7 to maintain repressed or active gene expression, respectively. A Fab-7 element is switched from a silenced to a mitotically heritable active state by an embryonic pulse of transcription. Here, histone H4 hyperacetylation was found to be associated with Fab-7 after activation, suggesting that H4 hyperacetylation may be a heritable epigenetic tag of the activated element. Activated Fab-7 enables transcription of a gene even after withdrawal of the primary transcription factor. This feature may allow epigenetic maintenance of active states of developmental genes after decay of their early embryonic regulators.

Acetylation↗
PubMed2001

Involvement of histone H4 acetylation in the epigenetic inheritance of different activity states of maternally and paternally derived genomes in the mealybug Planococcus citri.

Modification of histones by acetylation is a well-known mechanism for the establishment and maintenance of specific chromatin structures with different activity states. In Planococcus citri males the paternal genome, early in development, becomes mostly inactive and heterochromatic. As we had not found methylation in the genome of P. citri, we analyzed the acetylation state of histone H4. We report here that, in males, differences in the level of histone H4 acetylation are indeed present in the two genomes of different parental origin; these differences were confirmed by treatment with the histone deacetylase inhibitor Trichostatin A. There is also evidence of acetylation of histone H4 on metaphase chromosomes. Our data therefore suggest a role of histone H4 acetylation in the imprinting of the paternal genome in P. citri males, thus supporting a role of modification of chromatin-related structural proteins in the epigenetic transmission of imprinting.

Acetylation↗
PubMed1994

A Polycomb response element in the Ubx gene that determines an epigenetically inherited state of repression.

Segmentation genes provide the signals for the activation and regulation of homeotic genes in Drosophila but cannot maintain the resulting pattern of expression because their activity ceases halfway through embryogenesis. Maintenance of the pattern is due to the Polycomb group of genes (Pc-G) and the trithorax group of genes (trx-G), responsible for the persistence of the active or repressed state of homeotic genes. We have identified a regulatory element in the Ubx gene that responds to Pc-G and trx-G genes. Transposons carrying this element create new binding sites for Pc-G products in the polytene chromosomes. This Pc-G maintenance element (PRE), establishes a repressive complex that keeps enhancers repressed in cells in which they were originally repressed and maintains this state through many cell divisions. The trx-G products stimulate the expression of enhancers in cells in which they were originally active. This mechanism is responsible for the correct regulation of imaginal disc enhancers, which lack themselves antero-posterior positional information. The PRE also causes severe variegation of the mini-white gene present in the transposon, a phenomenon very similar to heterochromatic position-effect variegation. The significance of this mechanism for homeotic gene regulation is discussed.

Animals↗