Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Histone Modifications”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,531 records · Page 85Linked to original sources
PubMed2005

Nuclear proteins: promising targets for cancer drugs.

Recent progress in cancer drug therapy has recognized that the nucleus of the eukaryotic cell is an active site for many cellular processes important to the development of cancer. Many of these processes take place in specialized compartments of the nucleus. One of such sub-nuclear compartments is the promyelocytic leukemia nuclear body (PML NB). In acute promyelocytic leukemia (APL), PML forms a fusion protein with the retinoic acid receptor (RAR) alpha as a result of chromosomal translocation. This PML-RAR alpha fusion protein is responsible for the proliferative and de-differentiated phenotype of the leukemic cells and is the target of all-trans retinoic acid (ATRA). Another example of the specialized sub-nuclear compartments important in the targeting of cancer is the nucleolus. Recently, it has been proposed that the nucleolus serves as a stress sensor for the cell, and the molecular mechanism underlying this proposal has been discovered. Moreover, many anti-cancer drugs target specific protein-protein interactions within the nucleus. We will discuss current development surrounding two such target proteins: the hypoxia-inducible factor 1 alpha (HIF-1alpha) and FKBP25. Furthermore, chromatin structure, which is affected by modifications of core histones, has become a target of anti-cancer drugs. In this review, we will emphasize the significance of nuclear proteins as promising targets for cancer drug therapy by discussing a few key ideas, in three broad categories of specialized sub-nuclear compartments, protein-protein interactions, and the modifications of the chromatin structure.

Antineoplastic Agents↗
PubMed1985

Histone phosphorylation in native chromatin induces local structural changes as probed by electric birefringence.

In order to understand how the phosphorylation of histones affects the chromatin structure, we used electron microscopy, sedimentation velocity, circular dichroism and electric birefringence to monitor the salt-induced filament reversible solenoid transition of phosphorylated and native chromatin. Phosphorylation in vitro of chicken erythrocyte chromatin by cyclic-AMP-dependent protein kinase from porcine heart led to the modification of the histones H3 and H5 only, which were modified at a level of one phosphate and about three phosphate groups per molecule, respectively. In contrast to circular dichroism and sedimentation studies, which tend to suggest that phosphorylation of H3 and H5 does not affect chromatin structure, electron microscopy reveals that phosphorylation causes a relaxation of structure at low ionic strength. Electric birefringence and relaxation time measurements clearly prove that local structural changes are induced in chromatin: we observe a decrease of the steady-state birefringence with the appearance of a negative contribution in the signal and a marked increase of the flexibility of fibres. The component with the negative birefringence presents very short relaxation times, like those exhibited by small DNA fragments or individual nucleosomes. Two possibilities are then suggested. First, the conformational change is consistent with what would be expected from the presence of DNA segments loosely associated with the core histone H3. That the length of such segments could correspond to about one to two base-pairs per nucleosome strongly suggests that phosphorylation induces changes affecting some specific H3-DNA interactions only. This result could corroborate previous observations indicating that the N-terminal region of H3, where the site of phosphorylation is located, plays a decisive role in maintaining the superstructure of chromatin. Second, phosphorylation could introduce hinge points between each nucleosome. In this case, the negative birefringence results from partial orientation of the swinging nucleosomes. A possible mode of action of phosphorylation might be to weaken structural restraints imposed by histone H3, thus facilitating further condensation of chromatin.

Animals↗
PubMed2002

Acetylated, methylated, remodeled: chromatin states for gene regulation.

The activity state of a gene is determined not only by sequence-specific regulatory factors but also by a complex network of co-acting proteins. Many of these proteins directly or indirectly affect the structure of the chromatin environment into which the gene is embedded. Recent studies of histone and DNA modifications support and refine the concept of the chromatin environment being key to the establishment and maintenance of transcriptional activity or repression.

Acetylation↗
PubMed2004

Differential histone H3 Lys-9 and Lys-27 methylation profiles on the X chromosome.

Histone H3 tail modifications are among the earliest chromatin changes in the X-chromosome inactivation process. In this study we investigated the relative profiles of two important repressive marks on the X chromosome: methylation of H3 lysine 9 (K9) and 27 (K27). We found that both H3K9 dimethylation and K27 trimethylation characterize the inactive X in somatic cells and that their relative kinetics of enrichment on the X chromosome as it undergoes inactivation are similar. However, dynamic changes of H3K9 and H3K27 methylation on the inactivating X chromosome compared to the rest of the genome are distinct, suggesting that these two modifications play complementary and perhaps nonredundant roles in the establishment and/or maintenance of X inactivation. Furthermore, we show that a hotspot of H3K9 dimethylation 5' to Xist also displays high levels of H3 tri-meK27. However, analysis of this region in G9a mutant embryonic stem cells shows that these two methyl marks are dependent on different histone methyltransferases.

Animals↗
PubMed1991

Formation of nucleosomes on positively supercoiled DNA.

A transcribing RNA polymerase is thought to generate positive supercoils in front of the advancing transcription complex and negative supercoils behind. We have examined the possibility that positive supercoils might destabilize nucleosomes, facilitating transcription. We show that histone octamers bind to positively supercoiled DNA, and that after the complex is relaxed, 'classical' nucleosomes are present. We tested the possibility that nucleosomes on positively supercoiled DNA are in an altered (presumably more open) conformation, but revert to the classical structure only on release of this stress. However, circular dichroic spectra, and chemical cross-linking and modification of core histones, all suggest that the complexes initially formed on positively supercoiled DNA are classical nucleosomes. Although such structures are stable, their formation requires the plasmid to become more positively supercoiled, resulting in greater superhelical stress. In contrast, formation of nucleosomes on negatively supercoiled DNA relieves superhelical stress. In an exchange experiment in which equilibrium is achieved, nucleosomes transfer from positively to negatively supercoiled DNA, as predicted from the super-coiling free energies of the reactions. This suggests a mechanism for transcription of a gene assembled into chromatin, in which octamers are sequentially transferred from the region in front of the polymerase to the region behind.

Animals↗
PubMed2006

Erasure of histone acetylation by Arabidopsis HDA6 mediates large-scale gene silencing in nucleolar dominance.

Nucleolar dominance describes the silencing of one parental set of ribosomal RNA (rRNA) genes in a genetic hybrid, an epigenetic phenomenon that occurs on a scale second only to X-chromosome inactivation in mammals. An RNA interference (RNAi) knockdown screen revealed that the predicted Arabidopsis histone deacetylase, HDA6, is required for rRNA gene silencing in nucleolar dominance. In vivo, derepression of silenced rRNA genes upon knockdown of HDA6 is accompanied by nucleolus organizer region (NOR) decondensation, loss of promoter cytosine methylation, and replacement of histone H3 Lys 9 (H3K9) dimethylation with H3K4 trimethylation, H3K9 acetylation, H3K14 acetylation, and histone H4 tetra-acetylation. Consistent with these in vivo results, purified HDA6 deacetylates lysines modified by histone acetyltransferases whose substrates include H3K14, H4K5, and H4K12. HDA6 localizes, in part, to the nucleolus, supporting a model whereby HDA6 erases histone acetylation as a key step in an epigenetic switch mechanism that silences rRNA genes through concerted histone and DNA modifications.

Acetylation↗
PubMed2006

Histone H3.3 variant dynamics in the germline of Caenorhabditis elegans.

Germline chromatin undergoes dramatic remodeling events involving histone variants during the life cycle of an organism. A universal histone variant, H3.3, is incorporated at sites of active transcription throughout the cell cycle. The presence of H3.3 in chromatin indicates histone turnover, which is the energy-dependent removal of preexisting histones and replacement with new histones. H3.3 is also incorporated during decondensation of the Drosophila sperm pronucleus, indicating a direct role in chromatin remodeling upon fertilization. Here we present a system to monitor histone turnover and chromatin remodeling during Caenorhabditis elegans development by following the developmental dynamics of H3.3. We generated worm strains expressing green fluorescent protein- or yellow fluorescent protein-fused histone H3.3 proteins, HIS-71 and HIS-72. We found that H3.3 is retained in mature sperm chromatin, raising the possibility that it transmits epigenetic information via the male germline. Upon fertilization, maternal H3.3 enters both male and female pronuclei and is incorporated into paternal chromatin, apparently before the onset of embryonic transcription, suggesting that H3.3 can be incorporated independent of transcription. In early embryos, H3.3 becomes specifically depleted from primordial germ cells. Strikingly, the X chromosome becomes deficient in H3.3 during gametogenesis, indicating a low level of histone turnover. These results raise the possibility that the asymmetry in histone turnover between the X chromosome and autosomes is established during gametogenesis. H3.3 patterns are similar to patterns of H3K4 methylation in the primordial germ cells and on the X chromosome during gametogenesis, suggesting that histone turnover and modification are coupled processes. Our demonstration of dynamic H3.3 incorporation in nondividing cells provides a mechanistic basis for chromatin changes during germ cell development.

Animals↗
PubMedDate not supplied

Inhibition of histone deacetylases: a new strategy to target epigenetic modifications for anticancer treatment.

The role of epigenetic modifications due to deregulated acetylation of nucleosomes with respect to its role in progression and etiology of human cancer is discussed. Among the mediators of these phenomena are the histone deacetylases, a class of enzymes consisting of at least two subfamilies with a total of at least 7 members in mammals. Depending on the cell-type, inhibition of HDACs in cancer cells can lead to transcriptional activation and silencing of about 2% of human genes, cell-cycle arrest and induction of apoptosis and differentiation in vitro and in vivo. This paper discusses several inhibitors of HDACs primarily derived from natural sources, their physiological consequences in different in vitro and in vivo cancer-related systems, their stage of preclinical and clinical development as well as their potential as antineoplastic agents. It is of paramount importance to elucidate the molecular mechanisms resulting in cell-cycle arrest, apoptosis or differentiation after inhibition of HDACs and to investigate the physiological function of the different HDAC isoenzymes and their deregulation in human cancers in order to devise optimized therapeutic intervention in cancer patients.

Acetylation↗
PubMed2005

DNA methylation and gene silencing in cancer.

Epigenetic changes such as DNA methylation act to regulate gene expression in normal mammalian development. However, promoter hypermethylation also plays a major role in cancer through transcriptional silencing of critical growth regulators such as tumor suppressor genes. Other chromatin modifications, such as histone deacetylation and chromatin-binding proteins, affect local chromatin structure and, in concert with DNA methylation, regulate gene transcription. The DNA methylation inhibitors azacitidine and decitabine can induce functional re-expression of aberrantly silenced genes in cancer, causing growth arrest and apoptosis in tumor cells. These agents, along with inhibitors of histone deacetylation, have shown clinical activity in the treatment of certain hematologic malignancies where gene hypermethylation occurs. This review examines alteration in DNA methylation in cancer, effects on gene expression, and implications for the use of hypomethylating agents in the treatment of cancer.

Antimetabolites, Antineoplastic↗
PubMed2006

Epigenetic regulation of metabolism in children born small for gestational age.

PURPOSE OF REVIEW: Epigenetic alterations are responsible for modulation of tissue-specific gene expression and genomic imprinting. Mechanisms include posttranslational modifications of core histones and DNA methylation. The review focuses on emerging data highlighting the potential for epigenetic modulation of gene expression in mediating early-life programming of increased risk of adult-onset disease. To illustrate these concepts, we focus on epigenetic programming of insulin resistance, obesity and type 2 diabetes, with emphasis on the potential role of the adipocyte and three of its products, fatty acids, leptin and tumour necrosis factor alpha. RECENT FINDINGS: Recent studies have highlighted potential mechanisms underlying epigenetic modification of tissue function that may predispose to later development of insulin resistance. These include altered regulation of adipocyte clonal expansion and terminal differentiation via epigenetic modification of peroxisome proliferator-activated receptor gamma, Foxo1 or cyclin D1 expression and signalling that, via altered adipocyte lipid sequestration, alters lipid delivery to nonadipose tissue and, therefore, insulin action or modification of adipokine or cytokine expression and signalling. Direct epigenetic modification of insulin action in muscle may be achieved through altered stearoyl-CoA desaturase 1 expression, which correlates with low fatty acid oxidation. SUMMARY: While poor early growth and an increased risk of type 2 diabetes in adulthood are undisputedly linked, the relative impact of environment or genotype remains unclear. Altered DNA methylation patterns could, potentially, serve as biomarkers for assessment of prognosis and could help in the development of prophylactic strategies.

Adipose Tissue↗
PubMed2006

Chromatin decondensation and nuclear reprogramming by nucleoplasmin.

Somatic cell nuclear cloning has repeatedly demonstrated striking reversibility of epigenetic regulation of cell differentiation. Upon injection into eggs, the donor nuclei exhibit global chromatin decondensation, which might contribute to reprogramming the nuclei by derepressing dormant genes. Decondensation of sperm chromatin in eggs is explained by the replacement of sperm-specific histone variants with egg-type histones by the egg protein nucleoplasmin (Npm). However, little is known about the mechanisms of chromatin decondensation in somatic nuclei that do not contain condensation-specific histone variants. Here we found that Npm could widely decondense chromatin in undifferentiated mouse cells without overt histone exchanges but with specific epigenetic modifications that are relevant to open chromatin structure. These modifications included nucleus-wide multiple histone H3 phosphorylation, acetylation of Lys 14 in histone H3, and release of heterochromatin proteins HP1beta and TIF1beta from the nuclei. The protein kinase inhibitor staurosporine inhibited chromatin decondensation and these epigenetic modifications with the exception of H3 acetylation, potentially linking these chromatin events. At the functional level, Npm pretreatment of mouse nuclei facilitated activation of four oocyte-specific genes from the nuclei injected into Xenopus laevis oocytes. Future molecular elucidation of chromatin decondensation by Npm will significantly contribute to our understanding of the plasticity of cell differentiation.

Animals↗
PubMed2004

Two distinct methods analyzing chromatin structure using centrifugation and antibodies to modified histone H3: both provide similar chromatin states of the Rit1/Bcl11b gene.

Chromatin state of a 2-Mb region harboring Rit1/Bcl11b on mouse chromosome 12 was examined using two distinct methods. One is ChIP assay examining the degree of enrichment with histone H3 methylated at lysine 9 (H3-mLys9) in chromatin and the other is H/E (heterochromatin/euchromatin) assay that measures a chromatin condensation state by using centrifugation. The ChIP assay showed that a 50-kb interval covering the gene and an upstream region constituted chromatin enriched with unmethylated H3-mLys9 in cells expressing Rit1 compared to cells not expressing Rit1. In contrast, regions other than the 50-kb interval did not show much difference in the enrichment between the two different types of cells. On the other hand, H/E assay of two expressing and two non-expressing tissues provided compatible fractionation patterns, suggesting that the chromatin condensation state detected by H/E assay is correlated with the chromatin state controlled by histone H3 tail modification linked to gene expression. These results indicate that the centrifugation-based H/E assay should provide a new approach to the regulation of chromatin structure with respect to its condensation state, complementing ChIP assays.

Animals↗
PubMed2003

A dimeric viral SET domain methyltransferase specific to Lys27 of histone H3.

Site-specific lysine methylation of histones by SET domains is a hallmark for epigenetic control of gene transcription in eukaryotic organisms. Here we report that a SET domain protein from Paramecium bursaria chlorella virus can specifically di-methylate Lys27 in histone H3, a modification implicated in gene silencing. The solution structure of the viral SET domain reveals a butterfly-shaped head-to-head symmetric dimer different from other known protein methyltransferases. Each subunit consists of a Greek-key antiparallel beta-barrel and a three-stranded open-faced sandwich that mediates the dimer interface. Cofactor S-adenosyl-L-methionine (SAM) binds at the opening of the beta-barrel, and amino acids C-terminal to Lys27 in H3 and in the flexible C-terminal tail of the enzyme confer the specificity of this viral histone methyltransferase.

Amino Acid Sequence↗
PubMed2000

Chromatin-immune connections: regulation of MHC and other genes.

In cells, genes are contained within chromatin - a highly structured array of DNA wrapped around core histone proteins. Packaged genes are subject to a variety of regulatory modifications including, CpG methylation, histone acetylation and phosphorylation. These epigenetic mechanisms of gene regulation involve higher ordered protein complexes possessing enzymatic activities such as ATP hydrolysis and acetylation that are targeted to specific genes by transcription factors, coactivatorsand coreptessors. In this article, we endeavor to providean overview of current research on mechanisms of transcriptional regulation by chromatin remodeling of MHC and other genes that are of interest in reproductive immunology.

Animals↗
PubMed2002

The oncoprotein Set/TAF-1beta, an inhibitor of histone acetyltransferase, inhibits active demethylation of DNA, integrating DNA methylation and transcriptional silencing.

Histone hypoacetylation and DNA hypermethylation are hallmarks of gene silencing. Although a role for DNA methylation in regulating histone acetylation has been established, it is not clear how and whether epigenetic histone markings influence DNA modifications in transcriptional silencing. We have previously shown that induction of histone acetylation by trichostatin A promotes demethylation of ectopically methylated DNA (Cervoni, N., and Szyf, M. (2001) J. Biol. Chem. 276, 40778-40787). The oncoprotein Set/TAF-Ibeta is a subunit of the recently identified inhibitor of acetyltransferases complex that inhibits histone acetylation by binding to and masking histone acetyltransferase targets (Seo, S. B., McNamara, P., Heo, S., Turner, A., Lane, W. S., and Chakravarti, D. (2001) Cell 104, 119-130). We show here that the overexpression of Set/TAF-Ibeta, whose expression is up-regulated in multiple tumor tissues, inhibits demethylation of ectopically methylated DNA resulting in gene silencing. Overexpression of a mutant Set/TAF-Ibeta that does not inhibit histone acetylation is defective in inhibiting DNA demethylation. Taken together, these results are consistent with a novel regulatory role for Set/TAF-Ibeta, integrating epigenetic states of histones and DNA in gene regulation and provide a new mechanism that can explain how hypermethylation of specific regions might come about by inhibition of demethylation in cancer cells.

Acetyltransferases↗
PubMed2005

Rumex acetosa Y chromosomes: constitutive or facultative heterochromatin?

Condensed Y chromosomes in Rumex acetosa L. root-tip nuclei were studied using 5-azaC treatment and immunohistochemical detection of methylated histones. Although Y chromosomes were decondensed within root meristem in vivo, they became condensed and heteropycnotic in roots cultured in vitro. 5-azacytidine (5-azaC) treatment of cultured roots caused transitional dispersion of their Y chromosome bodies, but 7 days after removal of the drug from the culture medium, Y heterochromatin recondensed and again became visible. The response of Rumex sex chromatin to 5-azaC was compared with that of condensed segments of pericentromeric heterochromatin in Rhoeo spathacea (Sw.) Steam roots. It was shown that Rhoeo chromocentres, composed of AT-rich constitutive heterochromatin, did not undergo decondensation after 5-azaC treatment. The Y-bodies observed within male nuclei of R. acetosa were globally enriched with H3 histone, demethylated at lysine 4 and methylated at lysine 9. This is the first report of histone tail-modification in condensed sex chromatin in plants. Our results suggest that the interphase condensation of Y chromosomes in Rumex is facultative rather than constitutive. Furthermore, the observed response of Y-bodies to 5-azaC may result indirectly from demethylation and the subsequent altered expression of unknown genes controlling tissue-specific Y-inactivation as opposed to the global demethylation of Y-chromosome DNA.

Azacitidine↗
PubMed1980

Butyrate and related inhibitors of histone deacetylation block the induction of egg white genes by steroid hormones.

The short chain aliphatic acid salts, butyrate and propionate, are effective inhibitors of histone deacetylation in chick oviduct at 2--5 mM; they also prevent the hormonal induction of the ovalbumin and transferrin genes. The less potent deacetylase inhibitor isobutyrate is correspondingly less effective in blocking egg white mRNA induction; acetate has little effect at concentrations up to 15 mM. Butyrate does not appear to alter estrogen receptor binding in the nucleus, total RNA synthesis, or protein synthesis during the early hours of treatment when its specific effects on deacetylation and egg white gene transcription are observed. In addition to preventing the induction, butyrate also causes a rapid deinduction when added to preinduced cultures; ovalbumin and transferrin gene transcription decline with a half-life of 15--30 min. The effects of butyrate on egg white mRNA induction and deacetylation are completely reversible, and mRNA induction resumes within 1 hr after removal of butyrate from the medium. These results suggest that the modification of either histones or other unidentified regulatory proteins by acetylation may play a role in the mechanism of estrogen-mediated gene induction.

Acetylation↗
PubMed2005

The analysis of X-chromosome inactivation-related gene expression from single mouse embryo with sex-determination.

Chromatin remodeling by histone and DNA modification is important for the initiation of X-chromosome inactivation (XCI). In this study, a thorough transcriptional analysis of five XCI-related genes was performed by single cell reverse-transcribed PCR. An analysis of the XCI-related gene (Xist, Tsix, SUV39H1, SET7, and DNMT1) expression was performed to investigate the initiation process of XCI from early mouse single embryo (1-cell, 2-cell, 4-cell, 8-cell, and blastocyst). Detection of the expression of Xist and Tsix from single 2-cell embryo was feasible, although the expression of those genes was very low in single 1-cell embryo. Transcription of those genes may be activated from single 2-cell embryo. After determining the sex of single embryo by Y-chromosome-specific Zfy expression, we found that Tsix could be detected from both male and female single embryos, but it was only possible to detect Xist from female single embryo. XCI chromatin-remodeling genes, such as histone H3 methylation enzymes (SUV39H1 and SET7) and DNA methylation enzyme (DNMT1), were expressed during all early phases of embryogenesis. The expression of those genes in single embryo was not dependent on sex. Our study illustrated that the expression of these chromatin-remodeling genes, SUV39H1, DNMT1, and SET7, may be originated from germ cells, which were not dependent on zygotic activation of Xist from female single embryo.

Animals↗