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PubMed2004

A combination of different mass spectroscopic techniques for the analysis of dynamic changes of histone modifications.

The N-terminal tails of the histones are subject to many enzyme-mediated post-translational modifications, such as lysine acetylation, lysine and arginine methylation, serine phosphorylation, poly-ADP ribosylation and the attachment of the small peptide ubiquitin. These modifications, singly or in combination, are thought to generate an epigenetic code that specifies different patterns of gene activity. We present a detailed study on the mapping of histone post-translational modifications using a combination of matrix-assisted laser desorption/ionization-time of flight and electrospray ionization tandem mass spectrometry analysis of peptides generated by protease cleavage of individual histones isolated from different developmental stages. Due to their high content in basic amino acid residues and in order to be able to quantitatively compare two different samples we developed a chemical derivatization protocol. This strategy enabled us to determine the primary sequence of the peptides and to unambiguously assign specific modifications. This method is generally applicable to histone samples from various sources and can be used to study changes of modification patterns during early embryonic development or tissue differentiation and regeneration.

Amino Acid Sequence↗
PubMed2005

Silencing of human T-cell leukemia virus type I gene transcription by epigenetic mechanisms.

BACKGROUND: Human T-cell leukemia virus type I (HTLV-I) causes adult T-cell leukemia (ATL) after a long latent period. Among accessory genes encoded by HTLV-I, the tax gene is thought to play a central role in oncogenesis. However, Tax expression is disrupted by several mechanims including genetic changes of the tax gene, deletion/hypermethylation of 5'-LTR. To clarify the role of epigenetic changes, we analyzed DNA methylation and histone modification in the whole HTLV-I provirus genome. RESULTS: The gag, pol and env genes of HTLV-I provirus were more methylated than pX region, whereas methylation of 5'-LTR was variable and 3'-LTR was not methylated at all. In ATL cell lines, complete DNA methylation of 5'-LTR was associated with transcriptional silencing of viral genes. HTLV-I provirus was more methylated in primary ATL cells than in carrier state, indicating the association with disease progression. In seroconvertors, DNA methylation was already observed in internal sequences of provirus just after seroconversion. Taken together, it is speculated that DNA methylation first occurs in the gag, pol and env regions and then extends in the 5' and 3' directions in vivo, and when 5'-LTR becomes methylated, viral transcription is silenced. Analysis of histone modification in the HTLV-I provirus showed that the methylated provirus was associated with hypoacetylation. However, the tax gene transcript could not be detected in fresh ATL cells regardless of hyperacetylated histone H3 in 5'-LTR. The transcription rapidly recovered after in vitro culture in such ATL cells. CONCLUSION: These results showed that epigenetic changes of provirus facilitated ATL cells to evade host immune system by suppressing viral gene transcription. In addition, this study shows the presence of another reversible mechanism that suppresses the tax gene transcription without DNA methylation and hypoacetylated histone.

Carrier State↗
PubMed2026

ChIP-seq profiling identifies diapause-regulated H3K27me3 targets in the fat body of Culex pipiens.

Culex pipiens, a principal vector of significant arboviruses, survives winter through diapause, a hormonally controlled inactive phase that enhances endurance under severe cold circumstances. Recent data suggests that epigenetic processes, namely histone post-translational modifications (hPTMs), play a crucial role in regulating seasonal dormancy. Prior studies from our laboratory indicated a decrease in the methylation of Histone 3 (H3K27me3) in diapausing fat body tissue, associated with elevated expression of the histone demethylase UTX. Nonetheless, the precise genomic areas impacted by these chromatin alterations remained unidentified. We used chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq) to delineate the genome-wide distribution of H3K27me3 across fat body chromatin in diapausing (D) and non-diapausing (ND) female Cx. pipiens. Notably, the higher signal at transcription start sites (TSSs) reflects localized redistribution rather than a global decrease, as diapausing fat bodies retain less H3K27me3 overall but concentrate it at promoters. To investigate the functional significance of these chromatin alterations, we confirmed a number of target loci via ChIP-qPCR and assessed gene expression with qRT-PCR. We identified many critical genes that were markedly increased in diapausing mosquitoes, exhibiting an inverse relation to H3K27me3 enrichment. Our data demonstrates different H3K27me3 chromatin landscapes between diapausing and non-diapausing Cx. pipiens, corroborating a hypothesis of selective, locus-specific repression in the non-diapause state and its targeted removal during diapause to permit activation of dormancy-associated genes. These results suggest that chromatin remodeling is a core driver of the diapause switch.

Animals↗
PubMed2006

Genomic approaches to drug discovery.

Considerable progress has been made in exploiting the enormous amount of genomic and genetic information for the identification of potential targets for drug discovery and development. New tools that incorporate pathway information have been developed for gene expression data mining to reflect differences in pathways in normal and disease states. In addition, forward and reverse genetics used in a high-throughput mode with full-length cDNA and RNAi libraries enable the direct identification of components of signaling pathways. The discovery of the regulatory function of microRNAs highlights the importance of continuing the investigation of the genome with sophisticated tools. Furthermore, epigenetic information including DNA methylation and histone modifications that mediate important biological processes add to the possibilities to identify novel drug targets and patient populations that will benefit from new therapies.

Animals↗
PubMed2005

A new map for navigating the yeast epigenome.

The posttranslational modification of histones by acetylation or methylation regulates chromatin structure and can determine how a DNA sequence is interpreted by, for example, the transcriptional machinery. In this issue of Cell, Pokholok and colleagues (2005) describe a new and reliable genome-wide microarray study of histone modifications and gene expression in yeast. Their epigenetic map can be used to guide further research on the epigenome.

Chromosome Mapping↗
PubMedDate not supplied

Resetting the epigenetic histone code in the MRL-lpr/lpr mouse model of lupus by histone deacetylase inhibition.

The baseline level of gene expression varies between healthy controls and systemic lupus erythematosus (SLE) patients, and among SLE patients themselves. These variations may explain the different clinical manifestations and severity of disease observed in SLE. Epigenetic mechanisms, which involve DNA and histone modifications, are predictably associated with distinct transcriptional states. To understand the interplay between various histone modifications, including acetylation and methylation, and lupus disease, we performed differential expression histone modification analysis in splenocytes from the MRL-lpr/lpr mouse model of lupus. Using stable isotope labeling in combination with mass spectrometry, we found global site-specific hypermethylation (except H3 K4 methylation) and hypoacetylation in histone H3 and H4 MRL-lpr/lpr mice compared to control MRL/MPJ mice. Moreover, we have identified novel histone modifications such as H3 K18 methylation, H4 K31 methylation, and H4 K31 acetylation that are differentially expressed in MRL-lpr/lpr mice compared to controls. Finally, in vivo administration of the histone deacetylase inhibitor trichostatin A (TSA) corrected the site-specific hypoacetylation states on H3 and H4 in MRL-lpr/lpr mice with improvement of disease phenotype. Thus, this study is the first to establish the association between aberrant histone codes and pathogenesis of autoimmune disease SLE. These aberrant post-translational histone modifications can therefore be reset with histone deacetylase inhibition in vivo.

Amino Acid Sequence↗
PubMed1994

Perinatal hyperinsulinism as possible predisposing factor for diabetes mellitus, obesity and enhanced cardiovascular risk in later life.

The importance of the intrauterine and neonatal metabolic environment as possible teratogenic determinants of predispositions to diabetes, obesity and cardiovascular diseases is discussed. Epidemiological, clinical and experimental results suggest that gestational diabetes or even slightly impaired glucose tolerance during pregnancy are important risk factors for the development of an increased Type II- and even Type I diabetes susceptibility in the offspring. In addition, early prenatal undernutrition might also predispose to enhanced risk of Type II diabetes, whereas perinatal overnutrition seems to enhance predominantly Type I diabetes susceptibility. In this context, fetal and/or neonatal hyperinsulinism occurring during a critical period of brain development and leading to permanent malorganization of hypothalamic regulation centres for metabolism and hence to malprogramming of the hypothalamo-pancreatic system, is discussed as a possible reason for lifelong enhanced diabetes susceptibility. In view of epidemiological and experimental findings, an epigenetic maternofetal transmission of such acquired persistent modifications can run over several generations, mediated by gestational hyperglycaemia and fetal or neonatal hyperinsulinism. In conclusion, a partial prophylaxis of diabetes mellitus, obesity and cardiovascular diseases appears to be possible by prevention of gestational diabetes--even mild forms of impaired glucose tolerance during pregnancy--as well as early prenatal undernutrition and perinatal overnutrition.

Animals↗
PubMed2003

Strand-biased DNA methylation associated with centromeric regions in Arabidopsis.

The Arabidopsis genome project assembled 15 megabases of heterochromatic sequence, facilitating investigations of heterochromatin assembly, maintenance, and structure. In many species, large quantities of methylcytosine decorate heterochromatin; these modifications are typically maintained by methyltransferases that recognize newly replicated hemimethylated DNA. We assessed the extent and patterns of Arabidopsis heterochromatin methylation by amplifying and sequencing genomic DNA treated with bisulfite, which converts cytosine, but not methylcytosine, to uracil. This survey revealed unexpected asymmetries in methylation patterns, with one helix strand often exhibiting higher levels of methylation. We confirmed these observations both by immunoprecipitating methylated DNA strands and by restriction enzyme digestion of amplified, bisulfite-treated DNA. We also developed a primer-extension assay that can monitor the methylation status of an entire chromosome, demonstrating that strand-specific methylation occurs predominantly in the centromeric regions. Conventional models for methylation maintenance do not explain these unusual patterns; instead, new models that allow for strand specificity are required. The abundance of Arabidopsis strand-specific modifications points to their importance, perhaps as epigenetic signals that mark the heterochromatic regions that confer centromere activity.

Arabidopsis↗
PubMed2005

Down-regulation of human DAB2IP gene expression mediated by polycomb Ezh2 complex and histone deacetylase in prostate cancer.

Human DAB2IP (hDAB2IP), a novel GTPase-activating protein modulating the Ras-mediated signaling and tumor necrosis factor-mediated apoptosis, is a potent growth inhibitor in human prostate cancer (PCa). Loss of hDAB2IP expression in PCa is due to altered epigenetic regulation (i.e. DNA methylation and histone modification) of its promoter region. The elevated polycomb Ezh2, a histone methyltransferase, has been associated with PCa progression. In this study, we have demonstrated that an increased Ezh2 expression in normal prostatic epithelial cells can suppress hDAB2IP gene expression. In contrast, knocking down the endogenous Ezh2 levels in PCa by a specific small interfering RNA can increase hDAB2IP expression. The association of Ezh2 complex (including Eed and Suz12) with hDAB2IP gene promoter is also detected in PCa cells but not in normal prostatic epithelial cells. Increased Ezh2 expression in normal prostatic epithelial cells by cDNA transfection facilitates the recruitment of other components of Ezh2 complex to the hDAB2IP promoter region accompanied with the increased levels of methyl histone H3 (H3) and histone deacetylase (HDAC1). Consistently, data from PCa cells transfected with Ezh2 small interfering RNA demonstrated that reduced Ezh2 levels resulted in the dissociation of Ezh2 complex accompanied with decreased levels of both methyl H3 and HDAC1 from hDAB2IP gene promoter. We further unveiled that the methylation status of Lys-27 but not Lys-9 of H3 in hDAB2IP promoter region is consistent with the hDAB2IP levels in both normal prostatic epithelial cells and PCa cells. Together, we conclude that hDAB2IP gene is a target gene of Ezh2 in prostatic epithelium, which provides an underlying mechanism of the down-regulation of hDAB2IP gene in PCa.

Apoptosis↗
PubMed1998

A site- and strand-specific DNA break confers asymmetric switching potential in fission yeast.

Mating-type switching in the fission yeast Schizosaccharomyces pombe results in the transfer of genetic information from one of the two silent cassettes (mat2P or mat3M) to the transcriptionally active locus (mat1). The switching pattern is programmed by an imprinting event which restricts mat1 gene conversion to only one of the two sister cells, leading to asymmetric cell division. Biochemical analysis indicated that the mat1 locus contains a fragile chromosomal site. Southern hybridization and primer extension experiments showed that the fragility consists of a single-strand break (SSB). The nicked DNA is stable throughout the cell cycle. The features of the nick fulfil all the requirements for the 'epigenetic', site and strand-specific chromosome modification at the mat1 locus, providing strong evidence that an SSB can initiate mitotic and meiotic gene conversion during replication.

Cell Cycle↗
PubMed1999

Multiple antioxidants in the prevention and treatment of neurodegenerative disease: analysis of biologic rationale.

Parkinson's disease and Alzheimer's disease are major progressive neurologic disorders, the risk of which increases with advancing age (65 years and over). In familial cases, however, early onset of disease (35-65 years) is observed. In spite of extensive basic and chemical research on Parkinson's disease and Alzheimer's disease, no preventive or long-term effective treatment strategies are available. The analysis of existing literature suggests that oxidative stress is a major intermediary risk factor for the action of diverse groups of neurotoxins that are involved in these neurodegenerative diseases. In this review, it is proposed that the epigenetic components (mitochondria, other organelles, membranes, protein modification) rather than nuclear genes of neurons are the primary targets for the action of neurotoxins, including free radicals. In addition, a scientific rationale for using multiple antioxidants in clinical trials for the prevention of Parkinson's disease and Alzheimer's disease among high-risk populations, and as an adjunct to standard therapy in the treatment of these diseases is presented.

Alzheimer Disease↗
PubMed2005

Replication-independent core histone dynamics at transcriptionally active loci in vivo.

We used a novel labeling technique in the naturally synchronous organism Physarum polycephalum to examine the fate of core histones in G2 phase. We find rapid exchange of H2A/H2B dimers with free pools that is greatly diminished by treatment of the cells with alpha-amanitin. This exchange is enhanced in pol II-coding sequences compared with extragenic regions or inactive loci. In contrast, H3/H4 tetramers exhibit far lower levels of exchange in the pol II-transcribed genes tested, suggesting that tetramer exchange occurs via a distinct mechanism. However, we find that transcribed regions of the ribosomal RNA gene loci exhibit rapid exchange of H3/H4 tetramers. Thus, our data show that the majority of the pol II transcription-dependent histone exchange is due to elongation in vivo rather than promoter remodeling or other pol II-dependent alterations in promoter structure and, in contrast to pol I, pol II transcription through nucleosomes in vivo causes facile exchange of both H2A/H2B dimers while allowing conservation of epigenetic "marks" and other post-translational modifications on H3 and H4.

Amanitins↗
PubMed2006

Genomic imprinting and dermatological disease.

Imprinting is the process whereby genetic alleles responsible for a phenotype are derived from one parent only. It is an epigenetic phenomenon resulting from DNA methylation or modification of protruding histones. When imprinted genes are disrupted, syndromes with characteristic patterns of inheritance and multisystem phenotype occur. Those detailed in this article have some quite characteristic cutaneous features and patterns of inheritance. These diseases include Beckwith-Wiedmann, Silver-Russell, Prader-Willi, McCune-Albright and Angelman syndromes, Albright's hereditary osteodystrophy, and progressive osseous heteroplasia. In the case of Von Hippel-Lindau syndrome, hypomelanosis of Ito and dermatopathia pigmentosa reticularis, imprinting may play a part in the inheritance. With neurofibromatosis type 1, a nonimprinted condition, the expression of the phenotype could be affected by interaction with imprinted gene loci. Imprinted genes could also play a part in the polygenetic inheritance of more common diseases also, as atopic eczema and psoriasis may have predominantly maternal and paternal modes of transmission, respectively.

Angelman Syndrome↗
PubMed2006

Cathepsin L stabilizes the histone modification landscape on the Y chromosome and pericentromeric heterochromatin.

Posttranslational histone modifications and histone variants form a unique epigenetic landscape on mammalian chromosomes where the principal epigenetic heterochromatin markers, trimethylated histone H3(K9) and the histone H2A.Z, are inversely localized in relation to each other. Trimethylated H3(K9) marks pericentromeric constitutive heterochromatin and the male Y chromosome, while H2A.Z is dramatically reduced at these chromosomal locations. Inactivation of a lysosomal and nuclear protease, cathepsin L, causes a global redistribution of epigenetic markers. In cathepsin L knockout cells, the levels of trimethylated H3(K9) decrease dramatically, concomitant with its relocation away from heterochromatin, and H2A.Z becomes enriched at pericentromeric heterochromatin and the Y chromosome. This change is also associated with global relocation of heterochromatin protein HP1 and histone H3 methyltransferase Suv39h1 away from constitutive heterochromatin; however, it does not affect DNA methylation or chromosome segregation, phenotypes commonly associated with impaired histone H3(K9) methylation. Therefore, the key constitutive heterochromatin determinants can dynamically redistribute depending on physiological context but still maintain the essential function(s) of chromosomes. Thus, our data show that cathepsin L stabilizes epigenetic heterochromatin markers on pericentromeric heterochromatin and the Y chromosome through a novel mechanism that does not involve DNA methylation or affect heterochromatin structure and operates on both somatic and sex chromosomes.

Animals↗
PubMed2006

The testis-specific factor CTCFL cooperates with the protein methyltransferase PRMT7 in H19 imprinting control region methylation.

Expression of imprinted genes is restricted to a single parental allele as a result of epigenetic regulation-DNA methylation and histone modifications. Igf2/H19 is a reciprocally imprinted locus exhibiting paternal Igf2 and maternal H19 expression. Their expression is regulated by a paternally methylated imprinting control region (ICR) located between the two genes. Although the de novo DNA methyltransferases have been shown to be necessary for the establishment of ICR methylation, the mechanism by which they are targeted to the region remains unknown. We demonstrate that CTCFL/BORIS, a paralog of CTCF, is an ICR-binding protein expressed during embryonic male germ cell development, coinciding with the timing of ICR methylation. PRMT7, a protein arginine methyltransferase with which CTCFL interacts, is also expressed during embryonic testis development. Symmetrical dimethyl arginine 3 of histone H4, a modification catalyzed by PRMT7, accumulates in germ cells during this developmental period. This modified histone is also found enriched in both H19 ICR and Gtl2 differentially methylated region (DMR) chromatin of testis by chromatin immunoprecipitation (ChIP) analysis. In vitro studies demonstrate that CTCFL stimulates the histone-methyltransferase activity of PRMT7 via interactions with both histones and PRMT7. Finally, H19 ICR methylation is demonstrated by nuclear co-injection of expression vectors encoding CTCFL, PRMT7, and the de novo DNA methyltransferases, Dnmt3a, -b and -L, in Xenopus oocytes. These results suggest that CTCFL and PRMT7 may play a role in male germline imprinted gene methylation.

Animals↗
PubMed2005

Histone structure and nucleosome stability.

Histone proteins play essential structural and functional roles in the transition between active and inactive chromatin states. Although histones have a high degree of conservation due to constraints to maintain the overall structure of the nucleosomal octameric core, variants have evolved to assume diverse roles in gene regulation and epigenetic silencing. Histone variants, post-translational modifications and interactions with chromatin remodeling complexes influence DNA replication, transcription, repair and recombination. The authors review recent findings on the structure of chromatin that confirm previous interparticle interactions observed in crystal structures.

Animals↗
PubMed2005

Multiple-target drugs: inhibitors of heat shock protein 90 and of histone deacetylase.

In spite of the improvement of conventional medical therapy for cancer treatment, the impact on cancer related mortality in the last ten years has been modest especially for advanced disease in adults. On the other hand, understanding of molecular events underlining tumor development lead to the definition of new molecular targets for novel anti-tumor therapeutical approaches. On this regard, several biotechnology products selected by academic as well as industrial research are currently in clinical trials. Epigenetics as well as post-translational modifications of proteins are emerging as novel attractive targets for anticancer therapy. In addition, the heterogeneity of tumor cells within a selected neoplastic lesions as well as the redundancy of proliferative and survival pathways present in cancer cells favor the development of single drugs that are able to affect multiple pathways. Inhibitors of heat shock protein 90 and of histone deacetylase are two novel classes of multi-target agents that entered recently in clinical studies. This review will focus on the most important issues in the development of both these classes of agents.

Animals↗
PubMed2002

[The roles of DNA methylation in human neoplasms].

Recent data suggested that cancer appears to be a process that is fuelled both by genetic alterations and by epigenetic mechanisms. Epigenetics refer to the study of changes in gene expression that can be mitotically inherited, but is not associated with the changes in the coding sequence of the affected genes. DNA methylation, the best understood mechanism in epigenetics, is an enzyme-mediated chemical modification that adds methyl (CH3) groups at selected sites on DNA. In humans and most mammals, DNA methylation only affects the cytosine base (C), when it is followed by a guanosine (G). DNA methylation in the promoter regions is a powerful mechanism for the suppression of gene activity. It was thought formerly that two pathways by which tumor suppressor genes became disabled were intragenic mutations and loss of chromosomal material [(loss of heterozygosity (LOH) or homozygous deletion)]. More recent studies have firmly established methylation as one potential hit and represent a third mechanism by which tumor suppressor genes are inactivated, and that, in some cases, methylation is the sole mechanism responsible for the inactivation of a tumor suppressor gene. There is clearly a tumor-specific methylation pattern in many types of tumor. An individual tumor within a single patient may have characteristic set of gene with an increased propensity to become methylated as compared with a tumor of the same type in a different patient. Methylation changes appear to precede apparent malignancy in many cases. Therefore, methylation can distinguish tumor types and subtypes, and should be useful in improving early detection of potentially cancerous cells. Methylation markers may also be used to predict response to chemotherapy or duration of patient survival. The efficacy of hypomethylating agents (e.g. 5-aza-2'-deoxycytidine) as antineoplastic agents has been attributed to two distinct mechanism: cytotoxicity and induction of hypomethylation. Some clinical trials with them have been performed in solid tumors and malignant hematologic disease. In general, the response rates were not satisfactory. A variety of methods are used to evaluate the methylation status of genes. MSP (methylation-specific PCR) is very sensitive and has been widely used. It takes advantage of the DNA sequence difference existing between methylated and unmethylated DNA after bisulfite treatment.

CpG Islands↗