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PubMed2002

An epigenetic mouse model for molecular and behavioral neuropathologies related to schizophrenia vulnerability.

Reelin and glutamic acid decarboxylase (GAD)67 expressed by cortical gamma-aminobutyric acid-ergic interneurons are down-regulated in schizophrenia. Because epidemiological studies of schizophrenia fail to support candidate gene haploinsufficiency of Mendelian origin, we hypothesize that epigenetic mechanisms (i.e., cytosine hypermethylation of CpG islands present in the promoter of these genes) may be responsible for this down-regulation. Protracted l-methionine (6.6 mmolkg for 15 days, twice a day) treatment in mice elicited in brain an increase of S-adenosyl-homocysteine, the processing product of the methyl donor S-adenosyl-methionine, and a marked decrease of reelin and GAD67 mRNAs in both WT and heterozygous reeler mice. This effect of l-methionine was associated with an increase in the number of methylated cytosines in the CpG island of the reelin promoter region. This effect was not observed for GAD65 or neuronal-specific enolase and was not replicated by glycine doses 2-fold greater than those of l-methionine. Prepulse inhibition of startle declined at a faster rate as the prepulsestartle interval increased in mice receiving l-methionine. Valproic acid (2 mmolkg for 15 days, twice a day) reverted l-methionine-induced down-regulation of reelin and GAD67 in both WT and heterozygous reeler mice, suggesting an epigenetic action through the inhibition of histone deacetylases. The same dose of valproate increased acetylation of histone H3 in mouse brain nearly 4-fold. This epigenetic mouse model may be useful in evaluating drug efficacy on schizophrenia vulnerability. Hence the inhibition of histone deacetylases could represent a pharmacological intervention mitigating epigenetically induced vulnerability to schizophrenia in individuals at risk.

Acetylation↗

PubMed1997

Epigenetic changes at the insulin-like growth factor II/H19 locus in developing kidney is an early event in Wilms tumorigenesis.

Relaxation of imprinting at the insulin-like growth factor II (IFG-II)/H19 locus is a major mechanism involved in the onset of sporadic Wilms tumor and several other embryonal tumors. The high prevalence of histologically abnormal foci in kidney adjacent to Wilms tumors suggests that tumor-predisposing genetic/epigenetic lesion might also be found at high frequency in Wilms tumor-bearing kidneys. Focusing on Wilms tumors with relaxation of IFG-II imprinting, we determined the frequency of epigenetic change at the IFG-II/H19 locus in adjacent kidney. In all kidneys adjacent to these Wilms tumors, we detected substantial mosaicism for a population of cells with relaxation of IFG-II imprinting and biallelic H19 methylation, regardless of whether the patient had a tumor-predisposing syndrome or not. The high proportion of epigenetically modified cells among "normal" tissue indicates that the epigenetic error occurred very early in development, before the onset of Wilms tumor. Not only does this suggest that the major Wilms tumor-predisposing event occurs within the first few days of development, but it also suggests that sporadic Wilms tumor may represent one end of a spectrum of overgrowth disorders characterized by mosaic epigenetic change at the IFG-II/H19 locus.

Alleles↗

PubMed2004

Epigenetic silencing of the human nucleotide excision repair gene, hHR23B, in interleukin-6-responsive multiple myeloma KAS-6/1 cells.

During tumorigenesis, selective proliferative advantage in certain cell subsets is associated with accumulation of multiple genetic alterations. For instance, multiple myeloma is characterized by frequent karyotypic instability at the earliest stage, progressing to extreme genetic abnormalities as the disease progresses. These successive genetic alterations can be attributed, in part, to defects in DNA repair pathways, perhaps based on epigenetic gene silencing of proteins involved in DNA damage repair. Here we report epigenetic hypermethylation of the hHR23B gene, a key component of the nucleotide excision repair in response to DNA damage, in interleukin-6 (IL-6)-responsive myeloma KAS-6/1 cells. This hypermethylation was significantly abated by Zebularine, a potent demethylating agent, with a consequent increase in the hHR23B mRNA level. Subsequent removal of this drug and supplementation with IL-6 in the culture medium re-established DNA hypermethylation of the hHR23B gene and silencing of mRNA expression levels. The inclination of DNA to be remethylated, at least within the hHR23B gene promoter region, reflects an epigenetic driving force by the cytogenetic/tumorigenic status of KAS-6/1 myeloma. The IL-6 response of KAS-6/1 myeloma also raises a question of whether the proneoplastic growth factor, such as IL-6, supports the epigenetic silencing of important DNA repair genes via promoter hypermethylation during the development of multiple myeloma.

Base Sequence↗

PubMed2003

Discordance between genetic and epigenetic defects in pseudohypoparathyroidism type 1b revealed by inconsistent loss of maternal imprinting at GNAS1.

Although the molecular basis of pseudohypoparathyroidism type 1b (PHP type 1b) remains unknown, a defect in imprinting at the GNAS1 locus has been suggested by the consistent finding of paternal-specific patterns of DNA methylation on maternally inherited GNAS1 alleles. To characterize the relationship between the genetic and epigenetic defects in PHP type 1b, we analyzed allelic expression and methylation of CpG islands within exon 1A of GNAS1 in patients with sporadic PHP type 1b and in affected and unaffected individuals from five multigenerational kindreds with PHP type 1b. All subjects with resistance to parathyroid hormone (PTH) showed loss of methylation of the exon 1A region on the maternal GNAS1 allele and/or biallelic expression of exon 1A-containing transcripts, consistent with an imprinting defect. Paternal transmission of the disease-associated haplotype was associated with normal patterns of GNAS1 methylation and PTH responsiveness. We found that affected and unaffected siblings in one kindred had inherited the same GNAS1 allele from their affected mother, evidence for dissociation between the genetic and epigenetic GNAS1 defects. The absence of the epigenetic defect in subjects who have inherited a defective maternal GNAS1 allele suggests that the genetic mutation may be incompletely penetrant, and it indicates that the epigenetic defect, not the genetic mutation, leads to renal resistance to PTH in PHP type 1b.

Alleles↗

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↗

PubMed2026

Assessing the influence of different alignment tools on the accuracy of a forensic epigenetic clock.

MOTIVATION: DNA methylation (DNAm) has long been a commonly investigated biomarker in biomedical research. The current gold standard for DNAm detection is bisulfite sequencing which requires dedicated alignment tools that can handle reduced sequence complexity. One commonly used application of DNAm are epigenetic clock measurements. These clocks have been adapted by many fields for their specific needs, including forensic genetics. Here, epigenetic clocks were designed to help estimate the chronological age of a biological stain donor for investigative purposes. RESULTS: In this study, data generated with a well-established forensic epigenetic clock is aligned with four different bisulfite-specific alignment tools: "Bwa-meth," "Abismal," "Bismark," and "BS-Seeker2." For each tool, we tested up to six different settings, altering parameters such as the maximum number of mismatches or the score function setting. The goal was to investigate whether the final predicted ages differed considerably between the tested alignment tools and settings. Quality controls such as read depth, precision, recall, F1 score, and alignment run time were also assessed. To allow other researchers to easily perform such methylation comparison analyses on their own data, a Shiny app called "MethylAge Explorer" was developed within this study. None of the tested settings for the three alignment tools "Abismal," "Bismark," and "BS-Seeker2" outperformed the originally used alignment tool "Bwa-meth" in terms of age prediction accuracy. However, differences in final age predictions were observed between the different alignment tools. Therefore, it is necessary to be aware of which alignment tool to use for particular epigenetic clocks. AVAILABILITY AND IMPLEMENTATION: The data underlying this article and the code for the shiny app are available on GitHub (https://github.com/charlsut/methylage_explorer).

DNA Methylation↗

PubMed2001

A role for DNA polymerase alpha in epigenetic control of transcriptional silencing in fission yeast.

In the fission yeast Schizosaccharomyces pombe, transcriptional silencing at the mating-type region, centromeres and telomeres is epigenetically controlled, and results from the assembly of higher order chromatin structures. Chromatin proteins associated with these silenced loci are believed to serve as molecular bookmarks that help promote inheritance of the silenced state during cell division. Specifically, a chromodomain protein Swi6 is believed to be an important determinant of the epigenetic imprint. Here, we show that a mutation in DNA polymerase alpha (pol(alpha)) affects Swi6 localization at the mating-type region and causes a 45-fold increase in spontaneous transition from the silenced epigenetic state to the expressed state. We also demonstrate that pol(alpha) mutant cells are defective in Swi6 localization at centromeres and telomeres. Genetic analysis suggests that Polalpha and Swi6 are part of the same silencing pathway. Interestingly, we found that Swi6 directly binds to Pol(alpha) in vitro. Moreover, silencing-defective mutant Pol(alpha) displays reduced binding to Swi6 protein. This work indicates involvement of a DNA replication protein, Pol(alpha), in heterochromatin assembly and inheritance of epigenetic chromatin structures.

Amino Acid Sequence↗

PubMed2000

Developmental patterns of chromatin structure and DNA methylation responsible for epigenetic expression of a maize regulatory gene.

Epigenetic regulatory mechanisms heritably alter patterns of gene expression without changes in DNA sequence. Epigenetic states are often correlated with developmentally imposed alterations in genomic DNA methylation and local chromatin structure. Pl-Blotched is a stable epigenetic allele of the maize anthocyanin regulatory gene, purple plant1(pl). Pl-Blotched plants display a variegated pattern of pigmentation that contrasts sharply with the uniformly dark purple pigmentation of plants carrying the dominant Pl-Rhoades allele. Previously, we showed that the lower level of pigmentation in Pl-Blotched is correlated with lower pl mRNA levels and increased DNA methylation at some sites. To explore how DNA methylation, chromatin structure, and developmental stage might contribute to the expression of Pl-Blotched, we used methylation-sensitive restriction enzymes and DNaseI sensitivity assays to compare the methylation status and chromatin structure of Pl-Blotched and Pl-Rhoades at different stages in development. Both alleles exhibit developmentally sensitive changes in methylation. In Pl-Blotched, methylation of two diagnostic HpaII/MspI sites increases progressively, coincident with the juvenile-to-adult transition in growth. In seedlings, the chromatin encompassing the coding region of the gene is less sensitive to DNaseI digestion in Pl-Blotched than in Pl-Rhoades. Developmental maturation from seedling to adult is accompanied by expansion of this closed chromatin domain to include the promoter and downstream flanking sequences. We provide evidence to show that chromatin structure, rather than DNA methylation, is the primary epigenetic determinant for the phenotypic differences between Pl-Blotched and Pl-Rhoades.

Alleles↗

PubMed2005

Cancer epigenetics.

The field of cancer epigenetics is evolving rapidly on several fronts. Advances in our understanding of chromatin structure, histone modification, transcriptional activity and DNA methylation have resulted in an increasingly integrated view of epigenetics. In response to these insights, epigenetic therapy is expanding to include combinations of histone deacetylase inhibitors and DNA methyltransferase inhibitors. Zebularine, an orally administerable DNA methyltransferase inhibitor, has been a very promising recent addition to our arsenal of potentially useful drugs for epigenetic therapy. Aberrant DNA methylation patterns provide three powerful diagnostic applications as classification markers, sensitive detection markers, and risk assessment markers. Classification studies continue to increase in marker complexity, now incorporating microarrays, high-throughput bisulfite genomic sequencing and mass spectrometry, as the field moves to human epigenome projects. Sensitive detection technology has expanded from primarily blood-based cancer detection to include applications on a wide diversity of sample sources and is now also making inroads as a molecular risk assessment tool.

Antineoplastic Agents↗

PubMed2005

Diagnostic and therapeutic applications of epigenetics.

Epigenetic abnormalities, such as aberrant methylation of CpG islands, are inherited over cell divisions, and play important roles in carcinogenesis. Aberrant methylation of CpG islands specific to tumor cells can be used as a marker to detect cancer cells or cancer-derived DNA, taking advantage of the high sensitivity of methods to detect aberrant methylation. Methylations of specific genes or methylation patterns of groups of genes were found to be associated with responses to chemotherapeutics and prognosis. Methylation in non-cancerous tissues is now attracting attention as a tumor risk marker, and is emerging as a target for cancer prevention. Epigenetic alterations are potentially reversible. The use of DNA demethylating agents has turned out to be effective for hematological malignancies, and is being tested in solid tumors. Histone deacetylase inhibitors and methods for gene-specific epigenetic modification are being developed. Application of epigenetics to cancer diagnostics and therapeutics, and possibly to cancer prevention, is coming into clinics.

Biomarkers, Tumor↗

PubMed2002

Epigenetic variation and human disease.

Cytosine guanine dinucleotide (CpG) island methylation is a known mechanism of epigenetic inheritance in postmeiotic cells. Through associated chromatin changes and silencing, such epigenetic states can influence cellular physiology and affect disease risk and severity. Our studies of CpG island methylation in normal colorectal mucosa revealed progressive age-related increases at multiple gene loci, suggesting genome-wide molecular alterations with potential to silence gene expression. However, there was considerable variation in the degree of methylation among individuals of comparable ages. Such variation could be related to genetic factors, lifestyle, or environmental exposures. Studies in ulcerative colitis and hepatocellular cirrhosis and neoplasia revealed that chronic inflammatory states are accompanied by marked increases in CpG island methylation in normal-appearing tissues, confirming the hypothesis that proinflammatory exposures could account for part of the epigenetic variation in human populations. Preliminary data also suggest potential influences of lifestyle and exposure factors on CpG island methylation. It is suggested that epigenetic variation related to aging, lifestyle, exposures and possibly genetic factors, is one of the modulators of acquired, age-related human diseases, including neoplasia.

CpG Islands↗

PubMed2004

Tissue-specific and imprinted epigenetic modifications of the human NDN gene.

Allele-specific DNA methylation, histone acetylation and histone methylation are recognized as epigenetic characteristics of imprinted genes and imprinting centers (ICs). These epigenetic modifications are also used to regulate tissue-specific gene expression. Epigenetic differences between alleles can be significant either in the function of the IC or in the cis-acting effect of the IC on 'target' genes responding to it. We have now examined the epigenetic characteristics of NDN, a target gene of the chromosome 15q11-q13 Prader-Willi Syndrome IC, using sodium bisulfite sequencing to analyze DNA methylation and chromatin immunoprecipitation to analyze histone modifications. We observed a bias towards maternal allele-specific DNA hypermethylation of the promoter CpG island of NDN, independent of tissue-specific transcriptional activity. We also found that NDN lies in a domain of paternal allele-specific histone hyperacetylation that correlates with transcriptional state, and a domain of differential histone H3 lysine 4 di- and tri-methylation that persists independent of transcription. These results suggest that DNA methylation and histone H3 lysine 4 methylation are persistent markers of imprinted gene regulation while histone acetylation participates in tissue-specific activity and silencing in somatic cells.

Acetylation↗

PubMed2002

Epi-alleles in plants: inheritance of epigenetic information over generations.

Epigenetic modification of plant gene and transposon activity, which correlates with their methylation, is often heritable over many generations. Such heritable properties allow conventional genetic linkage analysis to identify the sequences affected in epigenetic variants. Machinery controlling the establishment of the epigenetic state and role of the epigenetic controls in plant development are also discussed.

Alleles↗

PubMed2001

Epigenetic regulation of the KAI1 metastasis suppressor gene in human prostate cancer cell lines.

Expression of the KAI1 gene, a metastasis-suppressor for prostate cancer, is reduced in all foci of prostatic metastasis. The altered regulatory mechanism is not strongly related to mutations or allelic losses of the KAI1 gene in prostate tumors. Since transcriptional silencing of genes has been found to be caused by epigenetic mechanisms, we have investigated the involvement of this epigenetic regulation of KAI1 expression in prostate cancers. The methylation status of the KAI1 promoter region was examined by restriction-enzyme digestion and sequencing, after amplifying a 331-bp fragment in the GC-rich promoter region from 4 human prostate cancer cell lines treated with bisulfite. The same 4 cell lines were also exposed to various concentrations of the demethylating agent, 5-aza-2'-deoxycytidine (5-AzaC) and / or the histone deacetylase inhibitor, trichostatin A (TSA). To clarify the influence of epigenetic modification on reduced KAI1 mRNA expression in the tumor cells, RT-PCR and northern-blot analyses were performed. Bisulfite-sequencing data showed a few methylated CpG islands in the promoter. RT-PCR analysis of 5-AzaC and / or TSA-treated cells indicated reversal of suppression of KAI1 transcription in two cell lines (PC-3 and DU-145), although the expression could not be detected by northern blots. From these results, it is suggested that epigenetic change is not the main mechanism of KAI1 down-regulation, though there remains a possibility that methylation in a more upstream region might be associated with this regulation.

Adenocarcinoma↗

PubMedDate not supplied

The epigenetic reprogramming of poorly aggressive melanoma cells by a metastatic microenvironment.

A dynamic, complex relationship exists between tumor cells and their microenvironment, which plays a pivotal role in cancer progression, yet remains poorly understood. Particularly perplexing is the finding that aggressive melanoma cells express genes associated with multiple cellular phenotypes, in addition to their ability to form vasculogenic-like networks in three-dimensional matrix--called vasculogenic mimicry, which is illustrative of tumor cell plasticity. This study addressed the unique epigenetic effect of the microenvironment of aggressive melanoma cells on the behavior of poorly aggressive melanoma cells exposed to it. The data show significant changes in the global gene expression of the cells exposed to 3-D matrices preconditioned by aggressive melanoma cells, including the acquisition of a vasculogenic cell phenotype, upregulation of ECM remodeling genes, and increased invasive ability--indicative of an epigenetic, microenvironment-induced reprogramming of poorly aggressive melanoma cells. However, this epigenetic effect was completely abrogated when a highly cross-linked collagen matrix was used, which could not be remodeled by the aggressive melanoma cells. These findings offer an unique perspective of the inductive properties associated with an aggressive melanoma microenvironment that might provide new insights into the epigenetic regulation of tumor cell plasticity and differentiation, as well as mechanisms that could be targeted for novel therapeutic strategies.

Cell Line, Tumor↗

PubMed2002

The relations between genetics and epigenetics: a historical point of view.

I have tried to unpack the polysemy of the word epigenetics by adopting a historical point of view and by focusing on the models that were proposed at the beginning of the 1960s to explain variations in gene activity during cell differentiation and development. Most of the questions that were or are at the core of epigenetics were posed in this period. This was due to the fact that the regulatory models and their extension to the notion of the genetic program were proposed as genetic answers to the questions raised by Waddington when he defined epigenetics in the 1940s. Studies of DNA methylation and chromatin structure, which became increasingly important in the 1960s and 1970s, were seen as alternative explanations to the regulatory mechanisms that had been previously proposed. This historical detour shows that epigenetics cannot be defined per se, but only as an evolving opposition to the piecemeal, reductionist approach of genetics.

Animals↗

PubMed2003

Epigenetics: the role of methylation in the mechanism of action of tumor suppressor genes.

Epigenetics is the study of mitotically heritable changes in gene expression without any changes in the primary DNA sequence. The major step in epigenetic gene regulation is gene inactivation by hypermethylation of CpG islands located in the promoter region. Specific enzymes and methylated DNA binding proteins play a major role in causing reduced expression of tumor suppressor genes, resulting in tumor formation and its progression. Prevention approaches are needed to avoid tumor formation. One approach to inhibiting inactivation of tumor suppressor genes is to use chemical agents such as 5-azacytidine to prevent hypermethylation of DNA. Increased understanding of the mechanism of epigenetic silencing and the identification of additional molecular mechanisms (e.g., histone methylases) that may be targeted by pharmaceutical interventions may lead to more preventive strategies. The current status of the epigenetic regulation of tumor suppressor genes is discussed in this review article.

DNA Methylation↗

PubMed2003

Epigenetics and the environment.

DNA methylation and histone modification promote changes in chromatin structure that may affect gene expression in a heritable manner without directly altering the genome. As such, these phenomena are considered to be epigenetic in nature and are believed to contribute to the normal processes of human development but also to aberrant disease states such as cancer. Epigenetic processes probably contribute mechanistically to toxicant-induced changes in gene expression and cancer. Nickel is a potent human carcinogen that has been shown to alter DNA methylation patterns and affect histone acetylation status. Both of these changes are associated with the proximity of the affected regions to heterochromatin. The two processes probably occur in concert in mammalian cells. However, in yeast cells, DNA methylation is absent, and nickel is capable of regulating gene expression through changes in acetylation of the lysine residues in the N terminal tail of histone H4. Arsenic is another important environmental carcinogen, and it is methylated during its metabolism. Hence, it has been proposed that arsenic metabolism may deplete intracellular methyl group stores and thereby lead to changes in DNA methylation that may be involved in carcinogenesis. However, the data concerning DNA methylation changes following arsenic exposure are equivocal, leading researchers to propose that DNA hypo- and hypermethylation are both important in the development of arsenic-induced cancers. Heightened awareness by toxicologists of the importance of epigenetics in normal human development and in carcinogenesis should lead to the identification of other toxicants that manifest their effects, at least in part, via epigenetic mechanisms.

Cocarcinogenesis↗