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PubMed2006

DNA methylation as a regulatory mechanism for gene expression in mammals.

Epigenetics refers to the study of heritable changes in gene expression that occur without a change in DNA sequence. In the last decade, it has been shown that epigenetic mechanisms provide an "extra" layer of transcriptional control that regulates genes expression. Three distinct mechanisms appear intricately related in initiating and sustaining epigenetic modifications: RNA-associated silencing, DNA methylation and histone modification. These mechanisms are critical components in the normal development and cell growth. DNA methylation is involved in transcriptional silencing of genes, regulation of expression of imprinted genes, a number of tumour suppressor genes in cancer and silencing of genes located on the inactive X chromosome. In this review, we are focused on the basic principles of DNA methylation as the main epigenetic mechanism for normal embryonic development and epigenetic alterations that contribute to carcinogenesis.

Animals↗
PubMed2006

[New therapeutic approaches for solid tumors: histone deacetylase, methyltransferase and proteasome inhibitors].

Recent results from basic and translational research on tumor genesis and progression establish the basis for future therapeutic approaches. Targeted therapeutics are tailored toward the molecular abnormalities that cause tumor progression and could potentially provide an effective, non-toxic therapeutic approach in a broad range of cancers including melanoma. Cancer is as much a (cyto)genetic disease as it is an epigenetic disease. Indeed, the fate of the cell depends on a delicate balance between expression and repression of genes. The notion that drastic changes in DNA methylation and histone modifications are present in a variety of human tumors has prompted the development and characterization of epigenetic drugs. Inhibitors of histone deacetylases and methyltransferases as well as of the proteasome are covered in this review.

Antineoplastic Agents↗
PubMed2003

Structural basis for histone and phosphohistone binding by the GCN5 histone acetyltransferase.

Distinct posttranslational modifications on histones occur in specific patterns to mediate certain chromosomal events. For example, on histone H3, phosphorylation at Ser10 can enhance GCN5-mediated Lys14 acetylation to promote transcription. To gain insight into the mechanism underlying this synergism, we determined the structure of Tetrahymena GCN5 (tGCN5) and coenzyme A (CoA) bound to unmodified and Ser10-phosphorylated 19 residue histone H3 peptides (H3p19 and H3p19Pi, respectively). The tGCN5/CoA/H3p19 structure reveals that a 12 amino acid core sequence mediates extensive contacts with the protein, providing the structural basis for substrate specificity by the GCN5/PCAF family of histone acetyltransferases. Comparison with the tGCN5/CoA/H3p19Pi structure reveals that phospho-Ser10 and Thr11 mediate significant histone-protein interactions, and nucleate additional interactions distal to the phosphorylation site. Functional studies show that histone H3 Thr11 is necessary for optimal transcription at yGcn5-dependent promoters requiring Ser10 phosphorylation. Together, these studies reveal how one histone modification can modulate another to affect distinct transcriptional signals.

Acetylation↗
PubMed2005

Distinct regulation of histone H3 methylation at lysines 27 and 9 by CpG methylation in Arabidopsis.

Transcriptional activity and structure of chromatin are correlated with patterns of covalent DNA and histone modification. Previous studies have revealed that high levels of histone H3 dimethylation at lysine 9 (H3K9me2), characteristic of transcriptionally silent heterochromatin in Arabidopsis, require hypermethylation of DNA at CpG sites. Here, we report that CpG hypermethylation characteristic of heterochromatin specifically prevented H3K27 trimethylation (H3K27me3). H3K27 mono- and dimethylation mark silent heterochromatin independently of DNA methylation. Upon loss of CpG methylation, there was target-specific enrichment of H3K27me3 in heterochromatin that correlated with transcriptional reactivation. Moreover, using the kyp mutant affected in H3K9me2, we showed that changes in H3K27me3 occurred independently of the levels of H3K9me2. Therefore, CpG methylation provides distinct and direct information for a specific subset of histone methylation marks. The observed independence of the regulation of H3K9 and H3K27 methylation by CpG methylation refines the recently proposed combinatorial histone code involving these two marks.

Arabidopsis↗
PubMed2002

Beyond the ABCs of CKC and SCC. Do centromeres orchestrate sister chromatid cohesion or vice versa?

The centromere-kinetochore complex is a highly specialized chromatin domain that both mediates and monitors chromosome-spindle interactions responsible for accurate partitioning of sister chromatids to daughter cells. Centromeres are distinguished from adjacent chromatin by specific patterns of histone modification and the presence of a centromere-specific histone H3 variant (e.g. CENP-A). Centromere-proximal regions usually correspond to sites of avid and persistent sister chromatid cohesion mediated by the conserved cohesin complex. In budding yeast, there is a substantial body of evidence indicating centromeres direct formation and/or stabilization of centromere-proximal cohesion. In other organisms, the dependency of cohesion on centromere function is not as clear. Indeed, it appears that pericentromeric heterochromatin recruits cohesion proteins independent of centromere function. Nonetheless, aspects of centromere function are impaired in the absence of sister chromatid cohesion, suggesting the two are interdependent. Here we review the nature of centromeric chromatin, the dynamics and regulation of sister chromatid cohesion, and the relationship between the two.

Animals↗
PubMed2005

[How to localize epigenetics in the landscape of biological research?].

Today, epigenetics is a very fashionable field of research. Modification of DNA by methylation, and of chromatin by histone modification or substitution represents a major fraction of the studies; but this special issue shows that epigenetic studies are very diverse, and not limited to the study of chromatin. What is common behind these different uses of the word epigenetics? A brief historical survey shows that epigenetics was invented twice, with different meanings: in the 1940s, by Conrad Waddington, as the study of the relations between the genotype and the phenotype; in the 1960s, as the global mechanisms of gene regulation involved in differentiation and development; what is common is that an approach distinct from genetics was in both cases considered as necessary because genetic models were incapable to address these problems. A good way to appreciate the relations between genetics and epigenetics is to realize that the main aim of organisms is to reproduce, and to consider the way organisms perform this task. Genetics is the precise means organisms have invented to reproduce the structure of their macromolecular components; the genome is also used to control the level and place of this reproduction. All the other means organisms have used to reproduce were more or less the result of tinkering, and constitute the field of epigenetics, with its diversity and richness.

Epigenesis, Genetic↗
PubMed2005

Effector proteins for methylated histones: an expanding family.

Methylation of histone lysine residues in eukaryotic chromatin has been an exciting area of research ever since the first histone methyltransferase enzyme, Suv39h, was found to methylate lysine 9 of histone H3 in 2000. Only a year later, the HP1 chromodomain polypeptide was identified as a recognition module for this histone modification. Similar to bromodomain-containing proteins that recognize histone acetylation sites and subsequently stabilize large complexes to chromatin, effector proteins can also be recruited and stabilized by histone methylation. Although histone acetylation generally correlates with active transcription, histone methylation is associated with both the activation and silencing of transcription, depending on which lysine residue is modified. The list of proteins that may in fact directly associate with specific methylated histone lysines is expanding. Since the finding of HP1, many additional proteins have been shown to bind methylated histone residues. For instance, Polycomb, Chd1, 53BP1, and Crb2/Rad9 proteins all associate with methylated chromatin in a unique manner governed by their respective recognition motifs. Here we highlight recent data on the recognition specificity and biological significance of proteins that associate with methylated histone lysines.

Carrier Proteins↗
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↗
PubMed1997

Changes in histone synthesis and modification at the beginning of mouse development correlate with the establishment of chromatin mediated repression of transcription.

The transition from a late 1-cell mouse embryo to a 4-cell embryo, the period when zygotic gene expression begins, is accompanied by an increasing ability to repress the activities of promoters and replication origins. Since this repression can be relieved by either butyrate or enhancers, it appears to be mediated through chromatin structure. Here we identify changes in the synthesis and modification of chromatin bound histones that are consistent with this hypothesis. Oocytes, which can repress promoter activity, synthesized a full complement of histones, and histone synthesis up to the early 2-cell stage originated from mRNA inherited from the oocyte. However, while histones H3 and H4 continued to be synthesized in early 1-cell embryos, synthesis of histones H2A, H2B and H1 (proteins required for chromatin condensation) was delayed until the late 1-cell stage, reaching their maximum rate in early 2-cell embryos. Moreover, histone H4 in both 1-cell and 2-cell embryos was predominantly diacetylated (a modification that facilitates transcription). Deacetylation towards the unacetylated and monoacetylated H4 population in fibroblasts began at the late 2-cell to 4-cell stage. Arresting development at the beginning of S-phase in 1-cell embryos prevented both the appearance of chromatin-mediated repression of transcription in paternal pronuclei and synthesis of new histones. These changes correlated with the establishment of chromatin-mediated repression during formation of a 2-cell embryo, and the increase in repression from the 2-cell to 4-cell stage as linker histone H1 accumulates and core histones are deacetylated.

Acetylation↗
PubMed2005

A decade of histone acetylation: marking eukaryotic chromosomes with specific codes.

Post-translational modification of histones, a major protein component of eukaryotic chromosomes, contributes to the epigenetic regulation of gene expression. Distinct patterns of histone modification are observed at specific chromosomal regions and affect various reactions on chromosomes (transcription, replication, repair, and recombination). Histone modification has long been proposed to have a profound effect on eukaryotic gene expression since its discovery in 1964. Verification of this idea, however, was difficult until the identification of enzymes responsible for histone modifications. Ten years ago (1995), histone acetyltransferases (HATs), which acetylate lysine residues in histone amino-terminal tail regions, were isolated. HATs are involved in the regulation of both promoter-specific transcription and long-range/chromosome-wide transcription. Analyses of HATs and other modification enzymes have revealed mechanisms of epigenetic regulation that are mediated by post-translational modifications of histones. Here we review some major advances in the field, with emphasis on the lysine specificity of the acetylation reaction and on the regulation of gene expression over broad regions.

Acetylation↗
PubMed2002

Signaling network model of chromatin.

We suggest that common principles underlie both cellular signaling networks and chromatin. To exemplify similarities, we focus on signaling complexes that form at membrane receptors and on nucleosomes. Multiple signal-transducing modifications on side chain residues of receptor tyrosine kinases (RTKs) and histone proteins are used to create docking sites that facilitate proximal relations of enzymes and their substrates. We argue that multiple histone modifications, like RTK modifications, promote switch-like behavior and ensure robustness of the signal, and we compare this interpretation with the histone code hypothesis. This view provides insight into chromatin function and epigenetic inheritance.

Animals↗
PubMed2003

Identification of novel histone post-translational modifications by peptide mass fingerprinting.

The extent and pattern of histone post-translational modifications is a key determinant dictating the structure of chromatin. We employed mass spectrometry to map the post-translational modifications present on mammalian core histones. Using accurate peptide mass fingerprinting on proteolytic digests of purified histones, we identified more than 20 novel sites of histone modification. One newly identified site of methylation, histone H4 lysine 59, maps to the surface of the nucleosome in close proximity to the site of the only identified histone core modification, histone H3 lysine 79. Consistent with the role of histone H3 lysine 79 methylation in the formation of silent chromatin structure, histone H4 lysine 59 is essential for transcriptional silencing at the yeast silent mating loci and telomeres.

Alanine↗
PubMed2005

Genome-wide dynamics of Htz1, a histone H2A variant that poises repressed/basal promoters for activation through histone loss.

Histone variants help specialize chromatin regions; however, their impact on transcriptional regulation is largely unknown. Here, we determined the genome-wide localization and dynamics of Htz1, the yeast histone H2A variant. Htz1 localizes to hundreds of repressed/basal Pol II promoters and prefers TATA-less promoters. Specific Htz1 deposition requires the SWR1 complex, which largely colocalizes with Htz1. Htz1 occupancy correlates with particular histone modifications, and Htz1 deposition is partially reliant on Gcn5 (a histone acetyltransferase) and Bdf1, an SWR1 complex member that binds acetylated histones. Changes in growth conditions cause a striking redistribution of Htz1 from activated to repressed/basal promoters. Furthermore, Htz1 promotes full gene activation but does not generally impact repression. Importantly, Htz1 releases from purified chromatin in vitro under conditions where H2A and H3 remain associated. We suggest that Htz1-bearing nucleosomes are deposited at repressed/basal promoters but facilitate activation through their susceptibility to loss, thereby helping to expose promoter DNA.

Acetylation↗
PubMed2006

Proline isomerization of histone H3 regulates lysine methylation and gene expression.

The cis-trans isomerization of proline serves as a regulatory switch in signaling pathways. We identify the proline isomerase Fpr4, a member of the FK506 binding protein family in Saccharomyces cerevisiae, as an enzyme which binds the amino-terminal tail of histones H3 and H4 and catalyses the isomerization of H3 proline P30 and P38 in vitro. We show that P38 is necessary for methylation of K36 and that isomerization by Fpr4 inhibits the ability of Set2 to methylate H3 K36 in vitro. These results suggest that the conformational state of P38, controlled by Fpr4, is important for methylation of H3K36 by Set2. Consistent with such an antagonistic role, abrogation of Fpr4 catalytic activity in vivo results in increased levels of H3K36 methylation and delayed transcriptional induction kinetics of specific genes in yeast. These results identify proline isomerization as a novel noncovalent histone modification that regulates transcription and provides evidence for crosstalk between histone lysine methylation and proline isomerization.

Amino Acid Sequence↗
PubMed2005

Aging: gene silencing or gene activation?

According to the author's theory of gene silencing, the key process in aging involves reduced expression of a number of genes. Silencing of genes has a complex mechanism, which involves methylation of DNA, histone modification and chromatin remodeling. In addition to deacetylation of the histones and methylation of DNA, recently described RNAi mechanism could initiate formation of silenced chromatin. Hypermethylation of the promoter will silence the gene. Genome-wide hypomethylation will induce genomic instability, amplification of oncogenes and also silencing of the genes through RNAi mechanism. Studies by different groups, conducted in yeast, worms, flies and mice, confirmed substantial changes in gene expression in aging. Among them, the most important was silencing of tumor suppressors and other genes involved in the control of cell cycle, apoptosis, detoxification, and cholesterol metabolism. There was also increased expression of the smaller group of oncogenes and other genes which are associated with typical diseases of old age. Caloric restriction normalizes expression of a substantial percentage of these genes. Animal studies confirmed importance of caloric restriction, which decreases signaling through the IGF-1/AKT pathway and expression of gene p53. These studies, however, cannot be directly applied to human aging. It is proposed that age management therapy should attempt to normalize gene expression in the older population to the level typical for young adults. This would require activation of silenced genes and normalization of overexpressed genes. Caloric restriction and exercise are helpful in decreasing the activity of important oncogenes and activation of silenced tumor suppressors, and may have a positive impact, not only on aging, but also on prevention of cancer. Dietary supplements containing phytochemicals should normalize increased expression of oncogenes. Examples are: genistein and EGCG, which effect signaling through the IGF-1/AKT pathway and resveratrol and limonen, which do so through the RAS pathway. A group of amino acid derivatives and organic acids of animal and human origin should activate silenced tumor suppressor genes (Aminocare A10, Aminocare Extra). Among them 3-phenylacetylamino-2, 6-piperidinedione intercalates specifically with DNA and protects sequences of tumor suppressor genes, which are vulnerable to the effects of carcinogens. Phenylacetate activates p53 and p21 through inhibition of methyltransferase and farnesylation of the RAS protein. Phenylbutyrate activates tumor suppressor genes through inhibition of histone deacetylation. Phenylacetylglutamine decreases genomic instability and expression of oncogenes and promotes apoptosis. The application of DNA microarray techniques to human studies should provide more information about differences in gene expression in different age groups and help design more effective age management regimens.

Adaptation, Physiological↗
PubMed2000

Histone H2A.Z regulats transcription and is partially redundant with nucleosome remodeling complexes.

Nucleosomes impose a block to transcription that can be overcome in vivo by remodeling complexes such as SNF/SWI and histone modification complexes such as SAGA. Mutations in the major core histones relieve transcriptional repression and bypass the requirement for SNF/SWI and SAGA. We have found that the variant histone H2A.Z regulates gene transcription, and deletion of the gene encoding H2A.Z strongly increases the requirement for SNF/SWI and SAGA. This synthetic genetic interaction is seen at the level of single genes and acts downstream of promoter nucleosome reorganization. H2A.Z is preferentially crosslinked in vivo to intergenic DNA at the PH05 and GAL1 loci, and this association changes with transcriptional activation. These results describe a novel pathway for regulating transcription using variant histones to modulate chromatin structure.

Adenosine Triphosphatases↗
PubMed2005

Characterization of lysine 56 of histone H3 as an acetylation site in Saccharomyces cerevisiae.

Post-translational histone modifications abound and regulate multiple nuclear processes. Most modifications are targeted to the amino-terminal domains of histones. Here we report the identification and characterization of acetylation of lysine 56 within the core domain of histone H3. In the crystal structure of the nucleosome, lysine 56 contacts DNA. Phenotypic analysis suggests that lysine 56 is critical for histone function and that it modulates formamide resistance, ultraviolet radiation sensitivity, and sensitivity to hydroxyurea. We show that the acetylated form of histone H3 lysine 56 (H3-K56) is present during interphase, metaphase, and S phase. Finally, reverse genetic analysis indicates that none of the known histone acetyltransferases is solely responsible for H3-K56 acetylation in Saccharomyces cerevisiae.

Alleles↗
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↗