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PubMed2006

Regulation of histone H2A and H2B ubiquitylation.

Histone ubiquitylation has emerged as an important chromatin modification with roles in transcription and trans-histone methylation. In the past several years, there has been dramatic progress in the identification of factors that control ubiquitin attachment to the core histones H2A and H2B. Recent advances in this area will be reviewed, and outstanding questions relating to the cellular functions of these modified histones will be discussed.

Animals↗
PubMed2006

Altered gene silencing and human diseases.

Epigenetic regulation of gene expression is mediated through several mechanisms, including modifications in DNA methylation, covalent modifications of core nucleosomal histones, rearrangement of histones and RNA interference. It is now clear that deregulation of epigenetic mechanisms cooperates with genetic alterations in the development and progression of several Mendelian disorders. Here, we summarize the recent findings that highlight how certain inherited diseases, such as Rett syndrome, Immunodeficiency-centromeric instability-facial anomalies syndrome, and facioscapulohumeral muscular dystrophy, result from altered gene silencing.

Animals↗
PubMed1977

The modification of nuclear proteins by ADP-ribosylation.

When incubated in vitro purified mouse nuclei incorporate NAD into poly(ADP-Rib). Analysis of the product on CsDl/urea gradients showed that a large proportion of the poly(ADP-Rib) was not attached to protein. The free poly(ADP-Rib) did not appear to arise through degradation and its chain length was significantly longer than the poly(ADP-Rib) attached to proteins. Fractionation of the proteins on hydroxyapatite revealed that tissue-specific modification of both the histones and non-histone proteins, had occurred. In the case of one protein species there was evidence for the existence of several forms with different numbers of ADP-Rib residues.

Animals↗
PubMed2001

Reactivation of the human cytomegalovirus major immediate-early regulatory region and viral replication in embryonal NTera2 cells: role of trichostatin A, retinoic acid, and deletion of the 21-base-pair repeats and modulator.

Inactivity of the human cytomegalovirus (HCMV) major immediate-early regulatory region (MIERR), which is composed of promoter, enhancer, unique region, and modulator, is linked to lack of HCMV replication in latently infected cells and in other nonpermissive cell types, including human embryonal NTera2 carcinoma (NT2) cells. I refined the embryonal NT2 cell model to enable characterization of the unknown mechanistic basis for silencing of HCMV MIERR-dependent transcription and viral replication in nonpermissive cells. These infected NT2 cells contain nonreplicating viral genomes with electrophoretic mobility equivalent to a supercoiled, bacterial artificial chromosome of comparable molecular weight. MIERR-dependent transcription is minimal to negligible. Increasing the availability of positive-acting transcription factors by retinoic acid (RA) treatment after infection is largely insufficient in reactivating the MIERR. In contrast, trichostatin A (TSA), a histone deacetylase inhibitor, reactivates MIERR-dependent transcription. Contrary to prior findings produced from transfected MIERR segments, deletion of the 21-bp repeats and modulator from the MIERR in the viral genome does not relieve MIERR silencing. To demonstrate that MIERR silencing likely results from enhancer inactivity, I examined an HCMV with a heterologous MIERR promoter that is enhancer dependent but exempt from IE2 p86-mediated negative autoregulation. This heterologous promoter, like its neighboring native MIERR promoter, exhibits immediate-early transcriptional kinetics in fibroblasts. In embryonal NT2 cells, the heterologous MIERR promoter is transcriptionally inactive. This silence is relieved by TSA but not by RA. Remarkably, TSA-induced reactivation of MIERR-dependent transcription from quiescent viral genomes is followed by release of infectious virus. I conclude that a mechanism of active repression imposes a block to MIERR-dependent transcription and viral replication in embryonal NT2 cells. Because TSA overcomes the block, viral gene silencing may involve histone deacetylase-based modification of viral chromatin, which might account for the covalently closed circular conformation of quiescent HCMV genomes.

Antigens, Viral↗
PubMed2005

Mutations in the nucleosome core enhance transcriptional silencing.

Transcriptional silencing in Saccharomyces requires specific nucleosome modifications promoted in part by a complex of Sir proteins that binds to the modified nucleosomes. Recent evidence suggests that modifications of both the histone amino termini and the core domain of nucleosomes contribute to silencing. We previously identified histone H4 mutations affecting residues in the core of the nucleosome that yield enhanced silencing at telomeres. Here we show that enhanced silencing induced by these mutations increases the proportion of cells in which telomeres and silent mating-type loci are in the silent state. One H4 mutation affects the expression of a subset of genes whose expression is altered by deletion of HTZ1, which encodes the histone variant H2A.Z, suggesting that the mutation may antagonize H2A.Z incorporation into nucleosomes. A second mutation causes the spread of silencing into subtelomeric regions that are not normally silenced in wild-type cells. Mechanistically, this mutation does not significantly accelerate the formation of silent chromatin but, rather, reduces the rate of decay of the silenced state. We propose that these mutations use distinct mechanisms to affect the dynamic interplay between activation and repression at the boundary between active and silent chromatin.

Alleles↗
PubMed2005

Chromatin architecture and functions: the role(s) of poly(ADP-RIBOSE) polymerase and poly(ADPribosyl)ation of nuclear proteins.

Epigenetic states that allow chromatin fidelity inheritance can be mediated by several factors. One of them, histone variants and their modifications (including acetylation, methylation, phosphorylation, poly(ADP-ribosyl)ation, and ubiquitylation) create distinct patterns of signals read by other proteins, and are strictly related to chromatin remodelling, which is necessary for the specific expression of a gene, and for DNA repair, recombination, and replication. In the framework of chromatin-controlling factors, the poly(ADP-ribosyl)ation of nuclear proteins, catalysed by poly(ADP-ribose)polymerases (PARPs), has been implicated in the regulation of both physiological and pathological events (gene expression/amplification, cellular division/differentiation, DNA replication, malignant transformation, and apoptotic cell death). The involvement of PARPs in this scenario has raised doubts about the epigenetic value of poly(ADP-ribosyl)ation, because it is generally activated after DNA damage. However, one emerging view suggests that both the product of this reaction, poly(ADP-ribose), and PARPs, particularly PARP 1, play a fundamental role in recruiting protein targets to specific sites and (or) in interacting physically with structural and regulatory factors, through highly reproducible and inheritable mechanisms, often independent of DNA breaks. The interplay of PARPs with protein factors, and the combinatorial effect of poly(ADPribosyl)ation with other post-translational modifications has shed new light on the potential and versatility of this dynamic reaction.

Adenosine Diphosphate Ribose↗
PubMed2005

Epigenetic and chromatin modifiers as targeted therapy of hematologic malignancies.

Epigenetic regulation of gene expression is mediated through alterations in the DNA methylation status, covalent modifications of core nucleosomal histones, rearrangement of histones, and by RNA interference. It is now abundantly clear that deregulation of epigenetic mechanisms cooperates with genetic alterations in the development and progression of cancer and leukemia. Epigenetic deregulation affects several aspects of tumor cell biology, including cell growth, cell cycle control, differentiation, DNA repair, and cell death. This raises the strong possibility that reversing deregulated epigenetic mechanisms may be an effective treatment strategy for leukemia and cancer. This treatment strategy may either be designed to separately or collectively target the specific perturbations in the epigenetic mechanisms found in human hematologic malignancies. The following review describes our current understanding of the important deregulated epigenetic mechanisms and the preclinical and clinical development of epigenetic and chromatin modifiers in the therapy of these disorders.

Chromatin↗
PubMed1987

Modification of deoxyribonucleic acid-thyroid hormone receptor interaction by histones.

The effects of histones on receptor-DNA interaction were examined using an in vitro DNA-cellulose-binding assay of [125I]T3 receptor. H1 histones bound to DNA-cellulose strongly inhibited binding of receptor to DNA-cellulose. DNA-cellulose column chromatography showed that 80% of T3-binding activity attached to DNA-cellulose could be eluted using 1 mg H1 histone/ml at low ionic strength. The potent inhibitory activity of H1 histones on receptor-DNA binding was reversed by removal of H1 histones from DNA-cellulose or by removal of H1 histones from receptor. The interaction was specific for the DNA-binding activity of receptor, since H1 histones inhibit neither T3-binding activity nor core histone-binding activity of receptor. In contrast, low concentrations of core histones enhanced binding of T3 receptor to DNA-cellulose. This effect was also seen when DNA-cellulose was treated with core histones and then deprived of free core histones. The enhancement was reversed by removal of core histones bound to DNA-cellulose. A tryptic fragment of the receptor, which lost DNA-binding activity but retained hormone and core histone-binding activities, was capable of binding to DNA-cellulose in the presence of core histones. These data suggest that enhanced binding of receptor to DNA-cellulose by core histones is mediated through the core histone-binding activity of receptor. A heat-labile protein factor in nuclear extracts (possibly receptor itself) also enhanced receptor binding to DNA-cellulose. Our data suggest important roles of histones in the organization of nuclear thyroid hormone receptors in chromatin. Since H1 histone participates in condensation of chromatin and is enriched in transcriptionally inactive chromatin, inhibition of DNA-binding activity of receptor by H1 histone bound to DNA could explain the preferential binding of nuclear thyroid hormone receptor to transcriptionally active chromatin.

Animals↗
PubMed2004

Equilibrium interactions of corepressors and coactivators with agonist and antagonist complexes of glucocorticoid receptors.

Corepressors and coactivators can modulate the dose-response curve and partial agonist activity of glucocorticoid receptors (GRs) complexed with agonist and antagonist steroids, respectively, in intact cells. We recently reported that GR-antagonist complexes bind to the coactivator TIF2, (transcriptional intermediary factor 2), which is consistent with the whole-cell effects of coactivators being mediated by direct interactions with GR complexes. We now ask whether the whole-cell modulatory activity of corepressors also entails binding to both GR-agonist and -antagonist complexes and whether the association of corepressors and coactivators with GR complexes involves competitive equilibrium reactions. In mammalian two-hybrid assays with two different cell lines and in cell-free pull-down and whole-cell immunoprecipitation assays, the corepressors NCoR (nuclear receptor corepressor) and SMRT (silencing mediator of retinoid and thyroid hormone receptor) associate with agonist and antagonist complexes of GRs. Both N- and C-terminal regions of GR are needed for corepressor binding, which requires the CoRNR box motifs that mediate corepressor binding to other nuclear/steroid receptors. Importantly, whole-cell GR interactions with corepressors are competitively inhibited by excess coactivator and vice versa. However, the regions of the coactivator TIF2 that compete for GR binding to corepressor and coactivator are not the same, implying a molecular difference in GR association with coactivators and corepressors. Finally, when the whole-cell ratio of coactivators to corepressors is altered by selective cofactor binding to exogenous thyroid receptor beta +/- thyroid hormone, the GR dose-response-curve and partial agonist activity are appropriately modified. Such modifications are independent of histone acetylation. We conclude that mutually antagonistic equilibrium interactions of corepressors and coactivators modulate the dose-response curve and partial agonist activity of GR complexes in a manner that is responsive to the intracellular ratio of these two classes of cofactors. This modulation provides an attractive mechanism for differential control of gene expression during development, differentiation, homeostasis, and endocrine therapies.

Animals↗
PubMed2006

Multiscale modeling of nucleosome dynamics.

Nucleosomes form the fundamental building blocks of chromatin. Subtle modifications of the constituent histone tails mediate chromatin stability and regulate gene expression. For this reason, it is important to understand structural dynamics of nucleosomes at atomic levels. We report a novel multiscale model of the fundamental chromatin unit, a nucleosome, using a simplified model for rapid discrete molecular dynamics simulations and an all-atom model for detailed structural investigation. Using a simplified structural model, we perform equilibrium simulations of a single nucleosome at various temperatures. We further reconstruct all-atom nucleosome structures from simulation trajectories. We find that histone tails bind to nucleosomal DNA via strong salt-bridge interactions over a wide range of temperatures, suggesting a mechanism of chromatin structural organization whereby histone tails regulate inter- and intranucleosomal assemblies via binding with nucleosomal DNA. We identify specific regions of the histone core H2A/H2B-H4/H3-H3/H4-H2B/H2A, termed "cold sites", which retain a significant fraction of contacts with adjoining residues throughout the simulation, indicating their functional role in nucleosome organization. Cold sites are clustered around H3-H3, H2A-H4 and H4-H2A interhistone interfaces, indicating the necessity of these contacts for nucleosome stability. Essential dynamics analysis of simulation trajectories shows that bending across the H3-H3 is a prominent mode of intranucleosomal dynamics. We postulate that effects of salts on mononucleosomes can be modeled in discrete molecular dynamics by modulating histone-DNA interaction potentials. Local fluctuations in nucleosomal DNA vary significantly along the DNA sequence, suggesting that only a fraction of histone-DNA contacts make strong interactions dominating mononucleosomal dynamics. Our findings suggest that histone tails have a direct functional role in stabilizing higher-order chromatin structure, mediated by salt-bridge interactions with adjacent DNA.

Chromatin↗
PubMed2003

Visible light irradiation of ethidium bromide-stained interphase nuclei causes DNA-protein linking and structural stabilization of nucleoprotein complexes.

Fixation of DNA and proteins in the isolated rat hepatocyte nuclei stained with ethidium bromide and irradiated with visible light was analyzed in this study. It was shown that irradiation results in the following modifications of higher-level nucleoprotein complexes of interphase chromatin: (1) the complexes acquire resistance to decondensing treatments, which may be indicative of the formation of links between proteins or proteins and DNA in the chromatin; (2) the linking rate for both DNA and proteins is dose dependent; (3) the irradiation induces intermolecular link formation between DNA molecules, which brings about an increase in the average molecular weight of DNA fragments; (4) some modifications (dimerization, etc.) of histones and nonhistone proteins occur; and (5) histone proteins are not effectively cross-linked to DNA. The structural stabilization of interphase chromatin is possibly mediated by free radical-based mechanisms, whereas disulfide bonds seem to play no significant role in the cross-linking.

Animals↗
PubMedDate not supplied

[Chromatin structure, heterochromatin, and transposable genetic elements--are they from one team?].

Gene content proved to be less than expected in completely sequenced eukaryotic genomes. Moreover, gene number differs only three times between such distant organisms as human and Drosophila. Hence it is likely that the essential functional and structural differences between the two species mostly depend on the regulation of gene activity than on the set and quality of genes themselves. New data demonstrate that changes in chromatin structure play a greater role in the fine gene activity regulation than considered before. R.B. Khesin had foresaw many chromatin functions that only recently came to be recognized. Khesin was interested in genome inconstancy over his last years. A higher content of several important chromosomal proteins was recently revealed in chromatin of transposable genetic elements (TGE). The possible role of TGE in chromatin organization in the nucleus is considered.

Animals↗
PubMed1989

The ubiquitin-dependent proteolytic pathway: specificity of recognition of the proteolytic substrates.

Degradation of intracellular proteins via the ubiquitin system involves several steps. Initially, ubiquitin is covalently linked to the protein substrate in an ATP-dependent reaction. Following ubiquitin conjugation, the protein is selectively degraded with the release of free and reutilizable ubiquitin. Ubiquitin modification of a variety of protein targets within the cell appears to be important in a number of basic cellular functions. For example, modification of core nucleosomal histones may regulate gene expression at the level of chromatin structure. Ubiquitin attachment to cell surface proteins can play a role in the processes of cell-cell interaction and adhesion. Conjugation of ubiquitin to other, yet to be identified protein(s), is probably involved in the progression of cells from one stage to another in the cell cycle. Despite the considerable progress that has been made in elucidating the mode of action and roles of the ubiquitin pathway major problems remain unsolved. One problem of central importance is the issue of what determines the specificity of the ubiquitin ligation system for commitment of certain proteins to degradation. While a free alpha-amino group is one structural feature of the substrate recognized by the ligation system, it is certainly not the only one, and possibly not the predominant recognition marker. The scope of this review is to discuss recent developments in our understanding of the specificity and selection of substrates for conjugation and subsequent degradation via the ubiquitin system.

Animals↗
PubMed2003

Facile synthesis of site-specifically acetylated and methylated histone proteins: reagents for evaluation of the histone code hypothesis.

The functional capacity of genetically encoded histone proteins can be powerfully expanded by posttranslational modification. A growing body of biochemical and genetic evidence clearly links the unique combinatorial patterning of side chain acetylation, methylation, and phosphorylation mainly within the highly conserved N termini of histones H2A, H2B, H3, and H4 with the regulation of gene expression and chromatin assembly and remodeling, in effect constituting a "histone code" for epigenetic signaling. Deconvoluting this code has proved challenging given the inherent posttranslational heterogeneity of histone proteins isolated from biological sources. Here we describe the application of native chemical ligation to the preparation of full-length histone proteins containing site-specific acetylation and methylation modifications. Peptide thioesters corresponding to histone N termini were prepared by solid phase peptide synthesis using an acid labile Boc/HF assembly strategy, then subsequently ligated to recombinantly produced histone C-terminal globular domains containing an engineered N-terminal cysteine residue. The ligation site is then rendered traceless by hydrogenolytic desulfurization, generating a native histone protein sequence. Synthetic histones generated by this method are fully functional, as evidenced by their self-assembly into a higher order H3/H4 heterotetramer, their deposition into nucleosomes by human ISWI-containing (Imitation of Switch) factor RSF (Remodeling and Spacing Factor), and by enzymatic modification by human Sirt1 deacetylase and G9a methyltransferase. Site-specifically modified histone proteins generated by this method will prove invaluable as novel reagents for the evaluation of the histone code hypothesis and analysis of epigenetic signaling mechanisms.

Acetylation↗
PubMed2005

The Saccharomyces cerevisiae Piccolo NuA4 histone acetyltransferase complex requires the Enhancer of Polycomb A domain and chromodomain to acetylate nucleosomes.

Chromatin modification complexes are key gene regulatory factors which posttranslationally modify the histone component of chromatin with epigenetic marks. To address what features of chromatin modification complexes are responsible for the specific recognition of nucleosomes compared to naked histones, we have performed a functional dissection of the Esa1-containing Saccharomyces cerevisiae Piccolo NuA4 histone acetyltransferase complex. Our studies define the Piccolo determinants sufficient to assemble its three subunits into a complex as well as Piccolo determinants sufficient to specifically acetylate a chromatin template. We find that the conserved Enhancer of Polycomb A (EPcA) homology region of the Epl1 component and the N-terminal 165 amino acids of the Yng2 component of Piccolo are sufficient with Esa1 to specifically act on nucleosomes. We also find that the Esa1 chromodomain plays a critical role in Piccolo's ability to distinguish between histones and nucleosomes. In particular, specific point mutations in the chromodomain putative hydrophobic cage which strongly hinder growth in yeast greatly reduce histone acetyltransferase activity on nucleosome substrates, independent of histone methylation or other modifications. However, the chromodomain is not required for Piccolo to bind to nucleosomes, suggesting a role for the chromodomain in a catalysis step after nucleosome binding.

Acetylation↗
PubMed2000

Regulation of the homeodomain CCAAT displacement/cut protein function by histone acetyltransferases p300/CREB-binding protein (CBP)-associated factor and CBP.

The CCAAT displacement protein/cut homologue (CDP/cut) is a divergent homeodomain protein that is highly conserved through evolution and has properties of a potent transcriptional repressor. CDP/cut contains three conserved cut-repeat domains and a conserved homeobox, each involved in directing binding specificity to unique nucleotide sequence elements. Furthermore, CDP/cut may play a role as a structural component of chromatin through its direct interaction with nucleosomal DNA and association with nuclear matrix attachment regions. CDP/cut is cell-cycle regulated through interactions with Rb, p107, specific kinases and phosphatases directing the transcriptional activity of CDP/cut on such genes encoding p21(WAF1,CIP1), c-myc, thymidine kinase, and histones. Our previous studies indicate that CDP/cut is associated with histone deacetylase activity and is associated with a corepressor complex through interactions with histone deacetylases. Here, we report the interaction of CDP/cut with CBP and p300/CREB-binding protein-associated factor (PCAF) along with the modification of CDP/cut by the histone acetyltransferase PCAF. Acetylation of CDP/cut by PCAF is directed at conserved lysine residues near the homeodomain region and regulates CDP/cut function. These observations are consistent with the ability of CDP/cut to regulate genes as a transcriptional repressor, suggesting acetylation as a mechanism that regulates CDP/cut function.

Acetyltransferases↗
PubMed2000

Linker histone binding and displacement: versatile mechanism for transcriptional regulation.

In recent years, the connection between chromatin structure and its transcriptional activity has attracted considerable experimental effort. The post-translational modifications to both the core histones and the linker histones are finely tuned through interactions with transcriptional regulators and change chromatin structure in a way to allow transcription to occur. Here we review evidence for the involvement of linker histones in transcriptional regulation and suggest a scenario in which the reversible and controllable binding/displacement of proteins of this class to the nucleosome entry/exit point determine the accessibility of the nucleosomal DNA to the transcriptional machinery.

Acetylation↗
PubMed2006

The transcriptional repressor JHDM3A demethylates trimethyl histone H3 lysine 9 and lysine 36.

Post-translational modification of chromatin has profound effects on many biological processes including transcriptional regulation, heterochromatin organization, and X-chromosome inactivation. Recent studies indicate that methylation on specific histone lysine (K) residues participates in many of these processes. Lysine methylation occurs in three distinct states, having either one (me1), two (me2) or three (me3) methyl groups attached to the amine group of the lysine side chain. These differences in modification state have an important role in defining how methylated chromatin is recognized and interpreted. Until recently, histone lysine methylation was considered a stable modification, but the identification of histone demethylase enzymes has demonstrated the reversibility of this epigenetic mark. So far, all characterized histone demethylases show enzymatic activity towards lysine residues modified in the me1 or me2 state, leaving open the possibility that me3 constitutes an irreversible modification. Here we demonstrate that JHDM3A (jumonji C (JmjC)-domain-containing histone demethylase 3A; also known as JMJD2A) is capable of removing the me3 group from modified H3 lysine 9 (H3K9) and H3 lysine 36 (H3K36). Overexpression of JHDM3A abrogates recruitment of HP1 (heterochromatin protein 1) to heterochromatin, indicating a role for JHDM3A in antagonizing methylated H3K9 nucleated events. siRNA-mediated knockdown of JHDM3A leads to increased levels of H3K9 methylation and upregulation of a JHDM3A target gene, ASCL2, indicating that JHDM3A may function in euchromatin to remove histone methylation marks that are associated with active transcription.

Animals↗