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PubMed2003

Genetic and epigenetic alterations in sentinel lymph nodes metastatic lesions compared to their corresponding primary breast tumors.

The accumulation of genetic and epigenetic changes plays a pivotal role in tumor development and progression. In this study, we investigated these changes using comparative genomic hybridization and bisulfite polymerase chain reaction analysis for CpG island hypermethylation of the following genes: TP16, THBS2, E-Cadherin (ECAD), RARbeta2, MINT1, MINT2, and MINT31 in six paired primary breast tumors and their matched sentinel lymph nodes (SLN). The most frequent chromosomal alterations observed were the following: losses of 6q13 approximately q23 and 13q13 approximately q32 and gains of 9q31 approximately qter, 11p15 approximately q21, 12q23 approximately qter, and 20q12 approximately qter. Gain of 6p21 approximately pter was observed in the SLN but in none of the primary tumors. Overall, 71% (30/42) of the methylation measurements were identical between the primary tumors and the SLN. Of the six cases, two showed no differences between the primary tumors and SLN, one tumor with 4 of 7 genes hypermethylated in the primary tumor showed loss of all four hypermethylation events in the SLN, and the remaining three tumors showed loss of one methylation event and simultaneous gain of one to two methylation changes in the SLN. This is the first study reporting genetic and epigenetic alterations in breast sentinel lymph nodes compared to their corresponding primary tumors. Characterization of such alterations may lead to identification of initial events associated with the metastatic dissemination process.

Aged↗
PubMed1998

Epigenetic factors regulate the NPY expression in rat cortical neurons.

The NPY phenotype expressed in a subset of rat neocortical neurons is influenced by a variety of epigenetic factors. In the present study, we analyzed the role of synaptically driven spontaneous bioelectric (action potential) activity (SBA) and neurotrophic factors. Our model systems are organotypic monocultures of visual cortex which either grow as spontaneously active cultures or as activity-blocked cultures to which neurotrophic factors can be applied via the medium. NPY mRNA expressing neurons are detected by in situ hybridization and are quantified as a percentage of all neurons. In spontaneously active cultures, about 7% of all neurons express NPY mRNA. This expression is regulated by SBA, because expression is reduced to about 2% by different activity blockade paradigms. When putative NPY neurons differentiate under activity blockade, they are unable to restitute the NPY expression during a subsequent period of SBA. A restitution of the NPY phenotype in 6-7% of the neurons after a transient blockade of activity is only possible when neurons were initially allowed to differentiate in the presence of SBA. We then analyzed whether neurotrophic factors known to promote NPY expression can do so in the absence of SBA. Neurotrophin-4/5 and leukemia inhibitory factor, but not brain-derived neurotrophic factor and neurotrophin-3, stimulate the NPY phenotype in the absence of SBA. In situ hybridization in combination with immuno-fluorescence reveals that NPY-ir neurons express the receptors trkB or LIFRbeta, but not trkC. This coexpression pattern explains why neurotrophin-4/5 and leukemia inhibitory factor are efficient regulators of the NPY-expression. Our results suggest that the NPY expression in neocortical neurons depends on epigenetic factors: spontaneous activity and neurotrophic factors modulate the expression and are thus involved in shaping the neurochemical architecture of the cerebral cortex.

Action Potentials↗
PubMed2001

Epigenetic mark sequence of the H19 gene in human sperm.

We have investigated the epigenetic mark in the human H19 gene. The H19 promoter is methylation-free in human sperm, but it is methylated in the paternally derived allele of most adult tissues. Consequently, the H19 gene is exclusively transcribed from the maternal allele. It was demonstrated that the differentially methylated region (DMR) located 2 kb upstream from mouse H19 is essential for the imprinting of H19. A 39 bp sequence in DMR has a high degree of similarity between humans, mice and rats. The highly conserved 15 bp core region of the consensus sequence contains four methylatable sites, and thus has been proposed as a potential imprinting mark region. In this study, fine epigenetic sequencing analysis was performed on the sperm DNA in comparison with other adult organs. Interestingly, the conserved sequence of the potential mark region was methylated in almost all the sperm genomes analyzed. Furthermore, the single dinucleotide CpG, whose methylation affects the accessibility of the element to CTCF, was methylated in the conserved core in the human sperm. These results suggest that the human core sequences may act as an imprinting center in the reciprocal monoallelic expression of H19.

Adult↗
PubMed2000

The epigenetics of nucleolar dominance.

Epigenetic phenomena are heritable, alternative states of gene activity that are not explained by mutation, changes in gene sequence or normal developmental regulation. Among the earliest examples was nucleolar dominance, a common phenomenon in interspecific hybrids in which only ribosomal RNA (rRNA) genes inherited from one parent are transcribed. Only active rRNA genes initiate formation of a nucleolus, hence the name for the phenomenon. As in other epigenetic phenomena, chromatin modifications enforce selective gene silencing in nucleolar dominance. However, the mechanisms that discriminate between parental sets of rRNA genes are unclear. Possibilities include sequence differences that affect transcription factor affinities. Other evidence suggests that chromosomal context is more important than rRNA gene sequences, implying control on a larger scale.

Cell Nucleolus↗
PubMed2001

Human morbid genetics revisited: relevance of epigenetics.

Identification of genes predisposing their carrier to complex diseases is a much more complicated task than finding genes involved in simple mendelian diseases. The slow progress in the genetic research of complex diseases could be due to limitations in the basic research strategy, which is almost exclusively orientated to the detection of disease-related DNA mutations or polymorphisms. I argue in this article that epigenetic misregulation of genes is more consistent with the features of complex diseases than is DNA sequence variation, and therefore that epigenetic factors could be important in understanding the origins of complex diseases.

Age of Onset↗
PubMed1997

The case for epigenetic effects on centromere identity and function.

The centromere is required to ensure the equal distribution of replicated chromosomes to daughter nuclei. Centromeres are frequently associated with heterochromatin, an enigmatic nuclear component that causes the epigenetic transcriptional repression of nearby marker genes (position-effect variegation or silencing). The process of chromosome segregation by movement along microtubules to spindle poles is highly conserved, yet the putative cis-acting centromeric DNA sequences bear little or no similarity across species. Recently, studies in several systems have revealed that the centromere itself might be epigenetically regulated and that the higher-order structure of the underlying heterochromatin contributes to centromere function and kinetochore assembly.

Animals↗
PubMed2000

DNA hypermethylation in tumorigenesis: epigenetics joins genetics.

Recently, the concept that epigenetic, as well as genetic, events might be central to the evolution of human cancer is re-emerging. Cancers often exhibit an aberrant methylation of gene promoter regions that is associated with loss of gene function. This DNA change constitutes a heritable state, not mediated by altered nucleotide sequence, that appears to be tightly linked to the formation of transcriptionally repressive chromatin. This epigenetic process acts as an alternative to mutations to disrupt tumor-suppressor gene function and can predispose to genetic alterations through inactivating DNA-repair genes. Dissecting the molecular processes that mediate these methylation changes will enhance our understanding of chromatin modeling and gene regulation and might present novel possibilities for cancer therapy. Methylation changes constitute potentially sensitive molecular markers to define risk states, monitor prevention strategies, achieve early diagnosis, and track the prognosis of cancer.

DNA Methylation↗
PubMed2000

Epigenetic aspects of cellular senescence.

The limited proliferative potential of normal cells in culture has been proposed as a model for cellular aging in vivo. It is clear that cellular aging has a genetic component but epigenetic processes could also be involved. Insight gained during years of intensive study suggests cellular aging is a multi-step process and that cells possess a counting mechanism that determines the number of doublings the cells can complete. In this paper, we review evidence suggesting a role for epigenetic processes in cell senescence and discuss the possible insights that might be provided by experiments designed to induce a premature senescent like state.

Biological Clocks↗
PubMed2001

Epigenetic targeting in the mouse zygote marks DNA for later methylation: a mechanism for maternal effects in development.

The transgenic sequences in the mouse line TKZ751 are demethylated on a DBA/2 inbred strain background but become highly methylated at postimplantation stages in offspring of a cross with a BALB/c female. In the reciprocal cross the transgene remains demethylated suggesting that imprinted BALB/c methylation modifiers or egg cytoplasmic factors are responsible for this striking maternal effect on de novo methylation. Reciprocal pronuclear transplantation experiments were carried out to distinguish between these mechanisms. The results indicate that a maternally-derived oocyte cytoplasmic factor from BALB/c marks the TKZ751 sequences at fertilization; this mark and postzygotic BALB/c modifiers are both required for de novo methylation of the target sequences at postimplantation stages. Using genetic linkage analyses we mapped the maternal effect to a locus on chromosome 17. Moreover, seven postzygotic modifier loci were identified that increase the postimplantation level of methylation. Analysis of interactions between the maternal and the postzygotic loci shows that both are needed for de novo methylation in the offspring. The combined experiments thus reveal a novel epigenetic marking process at fertilization which targets DNA for later methylation in the foetus. The most significant consequence is that the genotype of the mother can influence the epigenotype of the offspring by this marking process. A number of parental and imprinting effects may be explained by this epigenetic marking.

Alleles↗
PubMed1992

DNA reactive and epigenetic carcinogens.

Animal and human carcinogens exert their effects through diverse mechanisms which include DNA reaction and epigenetic effects. This review covers the basis for distinguishing between carcinogens that have either DNA reactivity or epigenetic activity as their primary effect.

Animals↗
PubMed2001

Histone methylation versus histone acetylation: new insights into epigenetic regulation.

Post-translational addition of methyl groups to the amino-terminal tails of histone proteins was discovered more than three decades ago. Only now, however, is the biological significance of lysine and arginine methylation of histone tails being elucidated. Recent findings indicate that methylation of certain core histones is catalyzed by a family of conserved proteins known as the histone methyltransferases (HMTs). New evidence suggests that site-specific methylation, catalyzed by HMTs, is associated with various biological processes ranging from transcriptional regulation to epigenetic silencing via heterochromatin assembly. Taken together, these new findings suggest that histone methylation may provide a stable genomic imprint that may serve to regulate gene expression as well as other epigenetic phenomena.

Acetylation↗
PubMed2003

Epigenetic gene regulation by noncoding RNAs.

Functional noncoding RNAs have distinct roles in epigenetic gene regulation. Large RNAs have been shown to control gene expression from a single locus (Tsix RNA), from chromosomal regions (Air RNA), and from entire chromosomes (roX and Xist RNAs). These RNAs regulate genes in cis; although the Drosophila roX RNAs can also function in trans. The chromatin modifications mediated by these RNAs can increase or decrease gene expression. These results suggest that the primary role of RNA molecules in epigenetic gene regulation is to restrict chromatin modifications to particular regions of the genome. However, given that RNA has been shown to be at the catalytic core of other ribonucleoprotein complexes, it is also possible that RNA also plays a role in modulating changes in chromatin structure.

Animals↗
PubMed1998

Chromo-domain proteins: linking chromatin structure to epigenetic regulation.

Chromo-domain proteins appear to be a central component in the epigenetic regulation of heterochromatin function and euchromatic gene expression. The recent discovery of a variety of interacting partners of chromo-domain proteins is yielding new molecular insights into epigenetic regulatory processes acting at the level of higher order chromatin structure.

Amino Acid Sequence↗
PubMed2002

Epigenetics: monoallelic expression in the immune system.

Epigenetic modifications to DNA and chromatin programme important genome functions including gene expression, chromosomal architecture and stability, and the maintenance of developmental states. Recent findings further implicate epigenetic modifications in the control of allelic choice in the immune system.

Alleles↗
PubMed2002

Epigenetic versus genetic alterations in the inactivation of E-cadherin.

Genetic mutation of genes that inhibit the formation of tumours has long been known to be one of the main driving forces in the development of cancer. Inactivation of one such gene, E-cadherin, is thought to be an important step in the development of most, or all, epithelial derived tumour types. Mutations within the E-cadherin gene have been identified as the cause of familial gastric cancer and loss of expression of E-cadherin has been found to be widespread in sporadically occurring epithelial tumours. Despite this, mutations of the E-cadherin gene have been only rarely found in most types of sporadic cancers. However, recent evidence has identified a second mechanism potentially responsible for inactivation of E-cadherin, and other important genes, during tumourigenesis, namely DNA methylation. This review will examine the importance of genetic (mutation) versus epigenetic (DNA methylation) mechanisms in the inactivation of E-cadherin during tumour development and also discuss potential differences in the functional consequences between inactivation by epigenetic or genetic means.

Cadherins↗
PubMed2000

Multiple links between the NuA4 histone acetyltransferase complex and epigenetic control of transcription.

NuA4 is an essential histone H4/H2A acetyltransferase complex that interacts with activators and stimulates transcription in vitro. We have identified three novel NuA4 subunits: Act3/Arp4, an actin-related protein implicated in epigenetic control of transcription, Act1, and Epl1, a protein homologous to Drosophila Enhancer of Polycomb. Act3/Arp4 binds nucleosomes in vitro and is required for NuA4 integrity in vivo. Mutations in ACT3 and acetyltransferase-encoding ESA1 cause gene-specific transcription defects. Accordingly, NuA4 is localized in precise loci within the nucleus and does not overlap with the silent chromatin marker Sir3. These data along with the known epigenetic roles of Act3/Arp4 and homologs of Epl1 and Esa1 strongly support an essential role for chromatin structure modification by NuA4 in transcription regulation in vivo.

Acetyltransferases↗
PubMed2002

Senescence and epigenetic dysregulation in cancer.

Mammalian cells have a finite proliferative lifespan, at the end of which they are unable to enter S phase in response to mitogenic stimuli. They undergo morphological changes and synthesize an altered repertoire of cell type-specific proteins. This non-proliferative state is termed replicative senescence and is regarded as a major tumor suppressor mechanism. The ability to overcome senescence and obtain a limitless replicative potential is called immortalization, and considered to be one of the prerequisites of cancer formation. While senescence mainly represents a genetically governed process, epigenetic changes in cancer have received increasing attention as an alternative mechanism for mediating gene expression changes in transformed cells. DNA methylation of promoter-containing CpG islands has emerged as an epigenetic mechanism of silencing tumor suppressor genes. New insights are being gained into the mechanisms causing aberrant methylation in cancer and evidence suggests that aging is accompanied by accumulation of cells with aberrant CpG island methylation. Aberrant methylation may contribute to many of the physiological and pathological changes associated with aging including tumor development. Finally, we describe how genes involved in promoting longevity might inhibit pathways promoting tumorigenesis.

Animals↗
PubMed2004

Zebularine: a candidate for epigenetic cancer therapy.

For many years, the search for cancer therapy targets focused on the genetic changes associated with the transformation of normal cells into malignant cells. However, it is now clear that disruptions in epigenetic mechanisms--modifications of DNA or histones that heritably alter gene expression without mutating DNA--are important in cancer. Zebularine is a stable DNA cytosine methylation inhibitor that is currently in development as an epigenetic therapy for cancer.

Antineoplastic Agents↗