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At least 469 records · Page 26Linked to original sources
PubMed2006

The effect of epigenetic sperm abnormalities on early embryogenesis.

Sperm are a highly specialized cell type derived to deliver the paternal haploid genome to the oocyte. The epigenetic, or gene regulatory, properties and mechanisms of the sperm assist in preparation of the paternal genome to contribute to embryogenesis and the genome of the zygote. Many recent studies have addressed the issue of altered epigenetic processes in the sperm. This review evaluates the current understanding of DNA damage, chromosome aneuploidy, reduced telomere length, malformations of the centrosome, genomic imprinting errors, altered mRNA profiles, and abnormal nuclear packaging in the sperm prior to fertilization and the observed effects on embryogenesis. Attention has also been given to understanding the underlying etiology of sperm with altered epigenetic mechanisms in humans.

Aneuploidy↗
PubMed2000

The epigenetics of colorectal cancer.

Colorectal cancer has provided an excellent model for studying the genetic basis of cancer and is one of the better-understood malignancies in this regard. The orderly progression of the disease, with distinct genetic alterations at each step, is a useful framework for deciphering the molecular basis of neoplasia. Epigenetics, the study of clonal changes in gene expression without associated genetic lesions, has raised increased interest recently, in part because of the identification of DNA methylation as a potential molecular mediator of the process. Several tumor-suppressor genes are silenced in various neoplasms in association with aberrant promoter methylation, and in the absence of coding region mutations. The study of DNA methylation changes in colorectal cancer has now provided additional clues into the pathogenesis of the disease. This review presents evidence for a model whereby DNA methylation changes play two distinct roles in the molecular evolution of colorectal cancer. Initially, progressive methylation and silencing of a subset of genes takes place in normal tissues as a function of age or time-dependent events and predisposes these normal cells to neoplastic transformation. At a later stage of disease progression, DNA methylation plays an important role in a subset of tumors affected by the CpG island methylator phenotype (CIMP), a recently identified pathway that results in a form of epigenetic instability through the simultaneous silencing of multiple genes. DNA methylation changes have important interactions with genetic lesions in this cancer type. CIMP+ cancers include the majority of tumors with sporadic mismatch repair deficiency through hypermethylation of the hMLH1 promoter, and also account for the majority of tumors with Ki-ras mutations through an unknown mechanism. By contrast, CIMP- cases evolve along a more classic genetic instability pathway, with a high rate of p53 mutations and chromosomal changes. Thus, the integration of epigenetic and genetic information provides a more complete molecular understanding of colorectal cancer and may have implications for the diagnosis, prognosis, and treatment of patients affected by this disease.

Adaptor Proteins, Signal Transducing↗
PubMed2002

What is "epi" about epigenetics?

What counts as epigenetic depends on what counts as genetic. It is argued that Weismannism, the doctrine of genetic continuity and somatic discontinuity, is the basis for an overly inclusive concept of epigenetics as every inherited resource "beyond the genes." An alternative theoretical perspective, the "reproducer" concept, is introduced to facilitate analysis of multiple inheritance systems without labeling all nongenetic inheritance "epigenetic."

Animals↗
PubMed2003

Promoter hypermethylation as an epigenetic component in Type I and Type II endometrial cancers.

Epigenetic mechanisms that result in aberrant gene expression are a prominent feature of many cancer types. One main epigenetic mechanism for gene silencing involves promoter hypermethylation. Type I and type II endometrial cancers exhibit differing clinical, histologic, and molecular genetic characteristics. We hypothesize that these differences also extend to epigenetic phenomena. Promoter methylation analysis of 11 genes in a panel of endometrial cancers supports this hypothesis. These initial data indicate that promoter hypermethylation events occur frequently in type 1 cancer and were not detected in type II cancers using this panel of loci. These data tend to support the hypothesis that type I and type II endometrial cancers will exhibit distinct patterns of gene silencing based on promoter hypermethylation events.

Cell Transformation, Neoplastic↗
PubMed2003

Epigenetics in carcinogenesis and cancer prevention.

Carcinogenesis is a stepwise process of accumulation of genetic and epigenetic abnormalities that can lead to cellular dysfunction. It has become clear that epigenetic changes are equally important for this multistep process to produce its results. This article describes the different roles that epigenetic modulation may play during carcinogenesis and how an early detection and chemopreventive intervention strategy that takes both sides of the equation into account would be advantageous.

Cell Transformation, Neoplastic↗
PubMed2003

Epigenetic changes: potential therapeutic targets.

Recent advances in human genome research have resulted in novel approaches for the identification of epigenetic modifications associated with cancer. Modulators of DNA methylation and chromatin structure have a dramatic effect on gene expression, cellular proliferation, differentiation, and apoptosis. Molecular pathways regulating epigenetic events that occur during tumorigenesis have been exploited as new targets for therapeutic intervention. Clinical studies exploring the effectiveness of therapeutic agents targeting DNA methylation and acetylation of histones have yielded promising results. Molecular profiles of epigenetic alterations in cancer cells could allow better stratification of patients who may show responsiveness to specific treatments.

Acetylation↗
PubMed2001

Nuclear cloning and epigenetic reprogramming of the genome.

Cloning of mammals by nuclear transfer (NT) results in gestational or neonatal failure with at most a few percent of manipulated embryos resulting in live births. Many of those that survive to term succumb to a variety of abnormalities that are likely due to inappropriate epigenetic reprogramming. Cloned embryos derived from donors, such as embryonic stem cells, that may require little or no reprogramming of early developmental genes develop substantially better beyond implantation than NT clones derived from somatic cells. Although recent experiments have demonstrated normal reprogramming of telomere length and X chromosome inactivation, epigenetic information established during gametogenesis, such as gametic imprints, cannot be restored after nuclear transfer. Survival of cloned animals to birth and beyond, despite substantial transcriptional dysregulation, is consistent with mammalian development being rather tolerant to epigenetic abnormalities, with lethality resulting only beyond a threshold of faulty gene reprogramming encompassing multiple loci.

Animals↗
PubMed2006

Analysis of human histone H2AZ deposition in vivo argues against its direct role in epigenetic templating mechanisms.

Chromatin is considered to be a principal carrier of epigenetic information due to the ability of alternative chromatin states to persist through generations of cell divisions and to spread on DNA. Replacement histone variants are novel candidates for epigenetic marking of chromatin. We developed a novel approach to analyze the chromatin environment of nucleosomes containing a particular replacement histone. We applied it to human H2AZ, one of the most studied alternative histones. We find that neither H2AZ itself nor other features of the H2AZ-containing nucleosome spread to the neighboring nucleosomes in vivo, arguing against a role for H2AZ as a self-perpetuating epigenetic mark.

Amino Acid Sequence↗
PubMed1998

Characterization of novel parent-specific epigenetic modifications upstream of the imprinted mouse H19 gene.

Genomic imprinting results in parent-specific monoallelic expression of a small number of genes in mammals. The identity of imprints is unknown, but much evidence points to a role for DNA methylation. The maternal alleles of the imprinted H19 gene are active and hypomethylated; the paternal alleles are inactive and hypermethylated. Roles for other epigenetic modifications are suggested by allele-specific differences in nuclease hypersensitivity at particular sites. To further analyze the possible epigenetic mechanisms determining monoallelic expression of H19, we have conducted in vivo dimethylsulfate and DNase I footprinting of regions upstream of the coding sequence in parthenogenetic and androgenetic embryonic stem cells. These cells carry only maternally and paternally derived alleles, respectively. We observed the presence of maternal-allele-specific dimethylsulfate and DNase I footprints at the promoter indicative of protein-DNA interactions at a CCAAT box and at binding sites for transcription factors Sp1 and AP-2. Also, at the boundary of a region further upstream for which existent differential methylation has been suggested to constitute an imprint, we observed a number of strand-specific dimethylsulfate reactivity differences specific to the maternal allele, along with an unusual chromatin structure in that both strands of maternally derived DNA were strongly hypersensitive to DNase I cutting over a distance of 100 nucleotides. We therefore reveal the existence of novel parent-specific epigenetic modifications, which in addition to DNA methylation, could constitute imprints or maintain monoallelic expression of H19.

Alleles↗
PubMed2002

Transcription through intergenic chromosomal memory elements of the Drosophila bithorax complex correlates with an epigenetic switch.

The proteins of the trithorax and Polycomb groups maintain the differential expression pattern of homeotic genes established by the early embryonic patterning system during development. These proteins generate stable and heritable chromatin structures by acting via particular chromosomal memory elements. We established a transgenic assay system showing that the Polycomb group response elements bxd and Mcp confer epigenetic inheritance throughout development. With previously published data for the Fab7 cellular memory module, we confirmed the cellular memory function of Polycomb group response elements. In Drosophila melanogaster, several of these memory elements are located in the large intergenic regulatory regions of the homeotic bithorax complex. Using a transgene assay, we showed that transcription through a memory element correlated with the relief of silencing imposed by the Polycomb group proteins and established an epigenetically heritable active chromatin mode. A memory element remodeled by the process of transcription was able to maintain active expression of a reporter gene throughout development. Thus, transcription appears to reset and change epigenetic marks at chromosomal memory elements regulated by the Polycomb and trithorax proteins. Interestingly, in the bithorax complex of D. melanogaster, the segment-specific expression of noncoding intergenic transcripts during embryogenesis seems to fulfill this switching role for memory elements regulating the homeotic genes.

Animals↗
PubMed2003

Transposable elements: targets for early nutritional effects on epigenetic gene regulation.

Early nutrition affects adult metabolism in humans and other mammals, potentially via persistent alterations in DNA methylation. With viable yellow agouti (A(vy)) mice, which harbor a transposable element in the agouti gene, we tested the hypothesis that the metastable methylation status of specific transposable element insertion sites renders them epigenetically labile to early methyl donor nutrition. Our results show that dietary methyl supplementation of a/a dams with extra folic acid, vitamin B(12), choline, and betaine alter the phenotype of their A(vy)/a offspring via increased CpG methylation at the A(vy) locus and that the epigenetic metastability which confers this lability is due to the A(vy) transposable element. These findings suggest that dietary supplementation, long presumed to be purely beneficial, may have unintended deleterious influences on the establishment of epigenetic gene regulation in humans.

Alleles↗
PubMed2005

Arginine methylation provides epigenetic transcription memory for retinoid-induced differentiation in myeloid cells.

Cellular differentiation is governed by changes in gene expression, but at the same time, a cell's identity needs to be maintained through multiple cell divisions during maturation. In myeloid cell lines, retinoids induce gene expression and a well-characterized two-step lineage-specific differentiation. To identify mechanisms that contribute to cellular transcriptional memory, we analyzed the epigenetic changes taking place on regulatory regions of tissue transglutaminase, a gene whose expression is tightly linked to retinoid-induced differentiation. Here we report that the induction of an intermediary or "primed" state of myeloid differentiation is associated with increased H4 arginine 3 and decreased H3 lysine 4 methylation. These modifications occur before transcription and appear to prime the chromatin for subsequent hormone-regulated transcription. Moreover, inhibition of methyltransferase activity, pre-acetylation, or activation of the enzyme PAD4 attenuated retinoid-regulated gene expression, while overexpression of PRMT1, a methyltransferase, enhanced retinoid responsiveness. Taken together, our results suggest that H4 arginine 3 methylation is a bona fide positive epigenetic marker and regulator of transcriptional responsiveness as well as a signal integration mechanism during cell differentiation and, as such, may provide epigenetic memory.

Acetylation↗
PubMed2005

Formation of an active tissue-specific chromatin domain initiated by epigenetic marking at the embryonic stem cell stage.

The differentiation potential of stem cells is determined by the ability of these cells to establish and maintain developmentally regulated gene expression programs that are specific to different lineages. Although transcriptionally potentiated epigenetic states of genes have been described for haematopoietic progenitors, the developmental stage at which the formation of lineage-specific gene expression domains is initiated remains unclear. In this study, we show that an intergenic cis-acting element in the mouse lambda5-VpreB1 locus is marked by histone H3 acetylation and histone H3 lysine 4 methylation at a discrete site in embryonic stem (ES) cells. The epigenetic modifications spread from this site toward the VpreB1 and lambda5 genes at later stages of B-cell development, and a large, active chromatin domain is established in pre-B cells when the genes are fully expressed. In early B-cell progenitors, the binding of haematopoietic factor PU.1 coincides with the expansion of the marked region, and the region becomes a center for the recruitment of general transcription factors and RNA polymerase II. In pre-B cells, E2A also binds to the locus, and general transcription factors are distributed across the active domain, including the gene promoters and the intergenic region. These results suggest that localized epigenetic marking is important for establishing the transcriptional competence of the lambda5 and VpreB1 genes as early as the pluripotent ES cell stage.

Acetylation↗
PubMed2005

Epigenetic mechanism of rRNA gene silencing: temporal order of NoRC-mediated histone modification, chromatin remodeling, and DNA methylation.

Epigenetic control mechanisms silence about half of the rRNA genes in eukaryotes. Previous studies have demonstrated that recruitment of NoRC, a SNF2h-containing remodeling complex, silences rRNA gene transcription. NoRC mediates histone H4 deacetylation, histone H3-Lys9 dimethylation, and de novo DNA methylation, thus establishing heterochromatic features at the rRNA gene promoter. Here we show that inhibition of any of these activities alleviates NoRC-dependent silencing, indicating that these processes are intimately linked. We have studied the temporal order of epigenetic events at the rRNA gene promoter during gene silencing and demonstrate that recruitment of NoRC by TTF-I is a prerequisite for the deacetylation of histone H4 and the dimethylation of histone H3-Lys9. Inhibition of histone deacetylation prevents DNA methylation, while inhibition of DNA methylation does not affect histone modification. Importantly, ATP-dependent chromatin remodeling is required for methylation of a specific CpG dinucleotide within the upstream control element of the rRNA gene promoter, and this modification impairs preinitiation complex formation. The results of this study reveal a clear hierarchy of epigenetic events that control de novo DNA methylation and lead to silencing of RNA genes.

Acetylation↗
PubMed2002

Mapping epigenetic quantitative trait loci (QTL) altering a developmental trajectory.

Genetic variation in a quantitative trait that changes with age is important to both evolutionary biologists and breeders. A traditional analysis of the dynamics of genetic variation is based on the genetic variance-covariance matrix among different ages estimated from a quantitative genetic model. Such an analysis, however, cannot reveal the mechanistic basis of the genetic variation for a growth trait during ontogeny. Age-specific genetic variance at time t conditional on the causal genetic effect at time t - 1 implies the generation of episodes of new genetic variation arising during the interval t - 1 to t. In the present paper, the conditional genetic variance estimated from Zhu's (1995) conditional model was partitioned into its underlying individual quantitative trait loci (QTL) using molecular markers in an F2 progeny of poplars (Populus trichocarpa and Populus deltoides). These QTL, defined as epigenetic QTL, govern the alterations of growth trajectory in a population. Three epigenetic QTL were detected to contribute significantly to variation in growth trajectory during the period from the establishment year to the subsequent year in the field. It is suggested that the activation and expression of epigenetic QTL are influenced by the developmental status of trees and the environment in which they are grown.

Analysis of Variance↗
PubMed2005

An epigenetic code for DNA damage repair pathways?

Exposure of living cells to intracellular or external mutagens results in DNA damage. Accumulation of DNA damage can lead to serious consequences because of the deleterious mutation rate resulting in genomic instability, cellular senescence, and cell death. To counteract genotoxic stress, cells have developed several strategies to detect defects in DNA structure. The eukaryotic genomic DNA is packaged through histone and nonhistone proteins into a highly condensed structure termed chromatin. Therefore the cellular enzymatic machineries responsible for DNA replication, recombination, and repair must circumvent this natural barrier in order to gain access to the DNA. Several studies have demonstrated that histone/chromatin modifications such as acetylation, methylation, and phosphorylation play crucial roles in DNA repair processes. This review will summarize the recent data that suggest a regulatory role of the epigenetic code in DNA repair processes. We will mainly focus on different covalent reversible modifications of histones as an initial step in early response to DNA damage and subsequent DNA repair. Special focus on a potential epigenetic histone code for these processes will be given in the last section. We also discuss new technologies and strategies to elucidate the putative epigenetic code for each of the DNA repair processes discussed.

Adenosine Diphosphate Ribose↗
PubMed2005

Epigenetic silencing of the MGMT gene in cancer.

Silencing of the O6-methylguanine-DNA methyltransferase (MGMT) gene, a key to DNA repair, plays a critical role in the development of cancer. The gene product, functioning normally, removes a methyl group from mutagenic O6-methylguanine, which is produced by alkylating agents and can make a mismatched pair with thymine, leading to transition mutation through DNA replication. MGMT is epigenetically silenced in various human tumors. It is well known that DNA hypermethylation at the promoter CpG island plays a pivotal role in the epigenetic silencing of tumor suppressor genes. MGMT silencing, however, occurs without DNA hypermethylation in some cancer cells. Dimethylation of histone H3 lysine 9 and binding of methyl-CpG binding proteins are common and essential in MGMT-silenced cells. Silencing of MGMT has been shown to be a poor prognostic factor but a good predictive marker for chemotherapy when alkylating agents are used. In this review, we describe recent advances in understanding the silencing of MGMT and its role in carcinogenesis; epigenetic mechanisms; and clinical implications.

CpG Islands↗
PubMed2004

Microarray analysis of epigenetic silencing of gene expression in the KAS-6/1 multiple myeloma cell line.

The epigenetic control of gene transcription in cancer has been the theme of many recent studies and therapeutic approaches. Carcinogenesis is frequently associated with hypermethylation and consequent down-regulation of genes that prevent cancer, e.g., those that control cell proliferation and apoptosis. We used the demethylating drug zebularine to induce changes in DNA methylation, then examined patterns of gene expression using cDNA array analysis and Restriction Landmark Genomic Scanning followed by RNase protection assay and reverse transcription-PCR to confirm the results. Microarray studies revealed that many genes were epigenetically regulated by methylation. We concluded that methylation decreased the expression of, or silenced, several genes, contributing to the growth and survival of multiple myeloma cells. For example, a number of genes (BAD, BAK, BIK, and BAX) involved in apoptosis were found to be suppressed by methylation. Sequenced methylation-regulated DNA fragments identified by Restriction Landmark Genomic Scanning were found to contain CpG islands, and some corresponded to promoters of genes that were regulated by methylation. We also observed that after the removal of the demethylating drug, the addition of interleukin 6 restored CpG methylation and re-established previously silenced gene patterns, thus implicating a novel role of interleukin 6 in processes regulating epigenetic gene repression and carcinogenesis.

Cell Line, Tumor↗