Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Histone Code”

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 109 records · Page 6Linked to original sources
PubMed2006

The necessity of a human epigenome project.

Epigenetics is one of the hottest topics in cancer research. We know that human tumors undergo a major disruption of their DNA methylation and histone modification patterns. The aberrant epigenetic landscape of the cancer cell is characterized by a massive genomic hypomethylation, CpG island promoter hypermethylation of tumor suppressor genes, an altered histone code for critical genes and a global loss of monoacetylated and trimethylated histone H4. But what we know is just a minimal percentage of the epigenetic 'earthquake' present in the transformed cell. We need to make an ambitious step to understand the DNA methylation and histone changes underlying tumorigenesis. The launching of an International Human Epigenome Project should be the response to this necessity.

CpG Islands↗
PubMed2003

Analysis of histone deposition on specific DNA elements in living mammalian cells.

DNA replication and repair involve the deposition of newly synthesized histones. After their deposition on a specific locus, histones are extensively modified on their protruding N-terminal tails to restore the histone code corresponding to this locus. These processes require a complex machinery of histone chaperones and histone-modifying enzymes. The precise kinetics of these events and the identity of the factors involved are still not clear. Here we present a technique based on transient expression of tagged histones followed by chromatin immunoprecipitation that allows the detection of newly synthesized histone deposition on specific DNA elements in mammalian cells at high resolution. This strategy could have important applications in chromatin dynamic studies.

Amino Acid Sequence↗
PubMed2005

Histone deacetylase inhibitors: a review of their clinical status as antineoplastic agents.

The histone code refers to specific modifications in the biochemical composition of nucleosome-associated histone proteins involved in the regulation of gene transcription. These modifications include, among several, acetylation, methylation, and phosphorylation of several histone amino acid residues and are associated with different states of chromatin configuration and gene expression. In particular, acetylation of specific residues in histones H3 and H4 has been associated with an open chromatin configuration and a permissive gene transcription state. This particular modification is regulated by several enzymatic activities with the capacity to either transfer acetyl groups or to induce histone deacetylation. This last activity is associated with gene silencing. Several agents have been shown to have histone deacetylase inhibitory activity (HDACI). In vitro, experiments in multiple neoplastic cancer cell lines have demonstrated that treatment with HDACIs results in increased global and gene specific histone acetylation, and reactivation of aberrantly silenced genes. This phenomenon has been associated with cell differentiation and induction of apoptosis. Based on these observations, several of these agents are now in clinical development both for solid tumor and hematological malignancies. In this article, we provide a brief introduction to the field of histone deacetylation inhibition in cancer and review the most relevant clinical data so far published.

Acetylation↗
PubMed2006

Epigenetic regulation during B cell differentiation controls CIITA promoter accessibility.

B cell to plasma cell maturation is marked by the loss of MHC class II expression. This loss is due to the silencing of the MHC class II transcriptional coactivator CIITA. In this study, experiments to identify the molecular mechanism responsible for CIITA silencing were conducted. CIITA is expressed from four promoters in humans, of which promoter III (pIII) controls the majority of B cell-mediated expression. Chromatin immunoprecipitation assays were used to establish the histone code for pIII and determine the differences between B cells and plasma cells. Specific histone modifications associated with accessible promoters and transcriptionally active genes were observed at pIII in B cells but not in plasma cells. A reciprocal exchange of histone H3 lysine 9 acetylation to methylation was also observed between B cells and plasma cells. The lack of histone acetylation correlated with an absence of transcription factor binding to pIII, particularly that of Sp1, PU.1, CREB, and E47. Intriguingly, changes in chromatin architecture of the 13-kb region encompassing all CIITA promoters showed a remarkable deficit in histone H3 and H4 acetylation in plasma cells, suggesting that the mechanism of silencing is global. When primary B cells were differentiated ex vivo, most of the histone marks associated with pIII activation and expression were lost within 24 h. The results demonstrate that CIITA silencing occurs by controlling chromatin accessibility through a multistep mechanism that includes the loss of histone acetylation and transcription factor binding, and the acquisition of repressive histone methylation marks.

B-Lymphocytes↗
PubMed1984

Variations in the organization of human genomic DNA segments containing H1 histone genes.

We have isolated from a lambda Ch4A library four human genomic DNA segments containing H1 histone genes. Analysis of the representation and organization of histone coding sequences indicates that three of these cloned DNA segments contain both core and H1 histone genes. One of the cloned human H1 histone genes has no core histone genes in close proximity.

Base Sequence↗
PubMed2002

The MYST domain acetyltransferase Chameau functions in epigenetic mechanisms of transcriptional repression.

Reversible acetylation of histone tails plays an important role in chromatin remodelling and regulation of gene activity. While modification by histone acetyltransferase (HAT) is usually linked to transcriptional activation, we provide here evidence for HAT function in several types of epigenetic repression. Chameau (Chm), a new Drosophila member of the MYST HAT family, dominantly suppresses position effect variegation (PEV), is required for the maintenance of Hox gene silencing by Polycomb group (PcG) proteins, and can partially substitute for the MYST Sas2 HAT in yeast telomeric position effect (TPE). Finally, we provide in vivo evidence that the acetyltransferase activity of Chm is required in these processes, since a variant protein mutated in the catalytic domain no longer rescues PEV modification, telomeric silencing of SAS2-deficient yeast cells, nor lethality of chm mutant flies. These findings emphasize the role of an acetyltransferase in gene silencing, which supports, according to the histone code hypothesis, that transcription at a particular locus is determined by a precise combination of histone tail modifications rather than by overall acetylation levels.

Acetyltransferases↗
PubMed1982

An unusual evolutionary behaviour of a sea urchin histone gene cluster.

DNA sequences of cloned histone coding sequences and spacers of sea urchin species that diverged long ago in evolution were compared. The highly repeated H4 and H3 genes active during early embryogenesis had evolved (in their silent sites) at a rate (0.5-0.6% base changes/Myr) similar to single-copy protein-coding genes and nearly as fast as spacer DNA (0.7% base changes/Myr) and unique DNA. Thus, evolution in the major histone genes conforms to a universal evolutionary clock based on the rate of base sequence change. By contrast, the H4 and H3 coding sequences and a non-transcribed spacer of the DNA clone h19 of Psammechinus miliaris show an exceptionally low rate of sequence evolution only 1/100 to 1/200 that predicted from the clock hypothesis. According to the classical model of gene inheritance, the h19 DNA sequences in the Psammechinus genome require unusual conservation mechanisms by selection at the level of the gene and spacer sequences. An alternative explanation could be recent horizontal gene transfer of a histone gene cluster from the very distantly related Strongylocentrotus dröbachiensis to the P. miliaris genome.

Journal Article↗
PubMed2005

Targeting the epigenome for the treatment and prevention of lung cancer.

Alterations in chromatin structure resulting from aberrant DNA methylation and perturbations of the histone code profoundly influence gene expression during pulmonary carcinogenesis. Recent studies indicate that DNA demethylating agents and histone deacetylase (HDAC) inhibitors synergistically induce gene expression and apoptosis in cultured lung cancer cells, and prevent lung cancer development in animals following exposure to tobacco carcinogens. Preliminary clinical trials have established proof of principle regarding the use of DNA demethylating agents and HDAC inhibitors for enhancing immunogenicity and apoptosis of lung cancer cells, and have revealed the complexities concerning the mechanisms by which chromatin remodeling agents mediate antitumor effects in vivo. These data support additional investigations pertaining to the epigenetics of lung cancer, and the evaluation of chromatin remodeling agents for the treatment and prevention of this disease.

Animals↗
PubMed1984

A new family of tandem repetitive early histone genes in the sea urchin Lytechinus pictus: evidence for concerted evolution within tandem arrays.

We have isolated and characterized a third nonallelic tandemly arrayed histone cluster (LpE) from the sea urchin Lytechinus pictus. Although this tandem array is not intermingled with the other two early histone gene families also found in the L. pictus genome, the order and polarity of the five histone coding sequences in this family are the same as every other well characterized sea urchin early histone gene family. Heteroduplex analysis and restriction endonuclease mapping experiments indicate that the LpE family is more closely related to the B-C than the A-D family of early histone genes. Examination of several individual sperm DNA samples has revealed considerable polymorphism in each of the three tandem repeat families. Within an individual, however, each family is remarkably homogeneous. Thus, our results indicate that rapid fixation of variants acts to homogenize the members of a single tandem array at a considerably faster rate within a family than between families. However, at least some exchange of sequences between families is evident based on the conservation of many restriction endonuclease recognition sites and from analysis of a a cosmid clone in which the A-D and E tandem repeats are found adjacent to one another. These differences in the rate of fixation of variants within and between these families are likely to be responsible for the maintenance of diversity between the different families.

Animals↗
PubMed2005

Rational development of histone deacetylase inhibitors as anticancer agents: a review.

The epigenome is defined by DNA methylation patterns and the associated post-translational modifications of histones. This histone code determines the expression status of individual genes dependent upon their localization on the chromatin. The histone deacetylases (HDACs) play a major role in keeping the balance between the acetylated and deacetylated states of chromatin and eventually regulate gene expression. Recent developments in understanding the cancer cell cycle, specifically the interplay with chromatin control, are providing opportunities for developing mechanism-based therapeutic drugs. Inhibitors of HDACs are under considerable exploration, in part because of their potential roles in reversing the silenced genes in transformed tumor cells by modulating transcriptional processes. This review is an effort to summarize the nonclinical and clinical status of HDAC inhibitors currently under development in anticancer therapy.

Animals↗
PubMed2002

Histone modifications in transcriptional regulation.

Covalent modifications of the amino termini of the core histones in nucleosomes have important roles in gene regulation. Research in the past two years reveals these modifications to consist of phosphorylation, methylation and ubiquitination, in addition to the better-characterized acetylation. This multiplicity of modifications, and their occurrence in patterns and dependent sequences, argues persuasively for the existence of a histone code.

Acetylation↗
PubMed2002

Structure of the Neurospora SET domain protein DIM-5, a histone H3 lysine methyltransferase.

AdoMet-dependent methylation of histones is part of the "histone code" that can profoundly influence gene expression. We describe the crystal structure of Neurospora DIM-5, a histone H3 lysine 9 methyltranferase (HKMT), determined at 1.98 A resolution, as well as results of biochemical characterization and site-directed mutagenesis of key residues. This SET domain protein bears no structural similarity to previously characterized AdoMet-dependent methyltransferases but includes notable features such as a triangular Zn3Cys9 zinc cluster in the pre-SET domain and a AdoMet binding site in the SET domain essential for methyl transfer. The structure suggests a mechanism for the methylation reaction and provides the structural basis for functional characterization of the HKMT family and the SET domain.

Amino Acid Sequence↗
PubMed2006

Statistical assessment of the global regulatory role of histone acetylation in Saccharomyces cerevisiae.

BACKGROUND: Histone acetylation plays important but incompletely understood roles in gene regulation. A comprehensive understanding of the regulatory role of histone acetylation is difficult because many different histone acetylation patterns exist and their effects are confounded by other factors, such as the transcription factor binding sequence motif information and nucleosome occupancy. RESULTS: We analyzed recent genomewide histone acetylation data using a few complementary statistical models and tested the validity of a cumulative model in approximating the global regulatory effect of histone acetylation. Confounding effects due to transcription factor binding sequence information were estimated by using two independent motif-based algorithms followed by a variable selection method. We found that the sequence information has a significant role in regulating transcription, and we also found a clear additional histone acetylation effect. Our model fits well with observed genome-wide data. Strikingly, including more complicated combinatorial effects does not improve the model's performance. Through a statistical analysis of conditional independence, we found that H4 acetylation may not have significant direct impact on global gene expression. CONCLUSION: Decoding the combinatorial complexity of histone modification requires not only new data but also new methods to analyze the data. Our statistical analysis confirms that histone acetylation has a significant effect on gene transcription rates in addition to that attributable to upstream sequence motifs. Our analysis also suggests that a cumulative effect model for global histone acetylation is justified, although a more complex histone code may be important at specific gene loci. We also found that the regulatory roles among different histone acetylation sites have important differences.

Acetylation↗
PubMed2004

Histone modification enzymes: novel targets for cancer drugs.

In eukaryotes, genomic DNA is packaged with histone proteins into the cell nucleus as chromatin, condensing the DNA > 10,000-fold. Chromatin is highly dynamic and exerts profound control on gene expression. Localised chromatin decondensation facilitates access of nuclear machinery. Chromatin displays epigenetic inheritance, in that changes in its structure can pass to the next generation independently of the DNA sequence itself. It is now clear that the post-translational modification of histones, for example, acetylation, methylation and phosphorylation, plays a crucial role in the regulation of nuclear function through the 'histone code'. There has been significant progress in identifying and understanding the enzymes that control these complex processes, in particular histone acetyltransferases and histone deacetylases. The exciting discovery that compounds inhibiting histone deacetylase activity also have antitumour properties has focused attention on their use as anticancer drugs. As a consequence, there is ongoing evaluation of several histone deacetylase inhibitor compounds in Phase I and II clinical trials with promising early results. It is likely that many of the enzymes involved in the control of histone modification will provide therapeutic opportunities for the treatment of cancer, including histone methyltransferases and Aurora kinases.

Acetylation↗
PubMed2006

Targeting histone deacetylase in cancer therapy.

Histone deacetylase (HDAC) is recognized as one of the promising targets for cancer treatment as many HDAC inhibitors have entered clinical trials for both solid and liquid tumors. Nevertheless, the mechanisms underlying the antiproliferative effects of HDAC inhibitors remain elusive. Although they have been shown to regulate the transcription of a defined set of genes through chromatin remodeling, increasing evidence suggests that modifications of the epigenetic histone code may not be the primary mechanism for HDAC inhibitor-mediated growth inhibition and apoptosis in cancer cells. While histones still represent a primary target for the physiological function of HDACs, the antitumor effect of HDAC inhibitors might also be attributed to transcription-independent mechanisms by modulating the acetylation status of a series of nonhistone targets. Also noteworthy is the effect of HDAC inhibitors on Akt downregulation through the alteration of protein phosphatase 1 (PP1) complex formation. To provide an overview of the use of HDAC inhibitors in cancer treatment, this review addresses the following subjects: (1) the physiological relevance of HDAC-mediated acetylation of histone and nonhistone substrates, (2) the chemical biology of HDACs and development of a novel class of HDAC inhibitors, and (3) the protein acetylation-independent effect of HDAC inhibitors on the activation status of signaling kinases.

Antineoplastic Agents↗
PubMed2006

The analysis of histone modifications.

The biological function of many proteins is often regulated through posttranslational modifications (PTMs). Frequently different modifications influence each other and lead to an intricate network of interdependent modification patterns that affect protein-protein interactions, enzymatic activities and sub-cellular localizations. One of the best-studied class of proteins that is affected by PTMs and combinations thereof are the histone molecules. Histones are very abundant, small basic proteins that package DNA in the eukaryotic nucleus to form chromatin. The four core-histones are densely modified within their first 20-40 N-terminal amino acids, which are highly evolutionary conserved despite playing no structural role. The modifications are thought to constitute a histone code that is used by the cell to encrypt various chromatin conformations and gene expression states. The analysis of modified histones can be used as a model to dissect complex modification patterns and to investigate their molecular functions. Here we review techniques that have been used to decipher complex histone modification patterns and discuss the implication of these findings for chromatin structure and function.

Amino Acid Sequence↗
PubMed2005

Histone acetylation-independent effect of histone deacetylase inhibitors on Akt through the reshuffling of protein phosphatase 1 complexes.

Despite advances in understanding the role of histone deacetylases (HDACs) in tumorigenesis, the mechanism by which HDAC inhibitors mediate antineoplastic effects remains elusive. Modifications of the histone code alone are not sufficient to account for the antitumor effect of HDAC inhibitors. The present study demonstrates a novel histone acetylation-independent mechanism by which HDAC inhibitors cause Akt dephosphorylation in U87MG glioblastoma and PC-3 prostate cancer cells by disrupting HDAC-protein phosphatase 1 (PP1) complexes. Of four HDAC inhibitors examined, trichostatin A (TSA) and HDAC42 exhibit the highest activity in down-regulating phospho-Akt, followed by suberoylanilide hydroxamic acid, whereas MS-275 shows only a marginal effect at 5 microm. This differential potency parallels the respective activities in inducing tubulin acetylation, a non-histone substrate for HDAC6. Evidence indicates that this Akt dephosphorylation is not mediated through deactivation of upstream kinases or activation of downstream phosphatases. However, the effect of TSA on phospho-Akt can be rescued by PP1 inhibition but not that of protein phosphatase 2A. Immunochemical analyses reveal that TSA blocks specific interactions of PP1 with HDACs 1 and 6, resulting in increased PP1-Akt association. Moreover, we used isozyme-specific small interfering RNAs to confirm the role of HDACs 1 and 6 as key mediators in facilitating Akt dephosphorylation. The selective action of HDAC inhibitors on HDAC-PP1 complexes represents the first example of modulating specific PP1 interactions by small molecule agents. From a clinical perspective, identification of this PP1-facilitated dephosphorylation mechanism underscores the potential use of HDAC inhibitors in lowering the apoptosis threshold for other therapeutic agents through Akt down-regulation.

Apoptosis↗
PubMed2003

Structural basis for specific binding of Polycomb chromodomain to histone H3 methylated at Lys 27.

The chromodomain of Drosophila Polycomb protein is essential for maintaining the silencing state of homeotic genes during development. Recent studies suggest that Polycomb mediates the assembly of repressive higher-order chromatin structures in conjunction with the methylation of Lys 27 of histone H3 by a Polycomb group repressor complex. A similar mechanism in heterochromatin assembly is mediated by HP1, a chromodomain protein that binds to histone H3 methylated at Lys 9. To understand the molecular mechanism of the methyl-Lys 27 histone code recognition, we have determined a 1.4-A-resolution structure of the chromodomain of Polycomb in complex with a histone H3 peptide trimethylated at Lys 27. The structure reveals a conserved mode of methyl-lysine binding and identifies Polycomb-specific interactions with histone H3. The structure also reveals a dPC dimer in the crystal lattice that is mediated by residues specifically conserved in the Polycomb family of chromodomains. The dimerization of dPC can effectively account for the histone-binding specificity and provides new mechanistic insights into the function of Polycomb. We propose that self-association is functionally important for Polycomb.

Amino Acid Sequence↗