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At least 1,639 records · Page 91Linked to original sources
PubMed2003

Partitioning and plasticity of repressive histone methylation states in mammalian chromatin.

Methylation of position-specific lysine residues in histone N termini is a central modification for regulating epigenetic transitions in chromatin. Each methylatable lysine residue can exist in a mono-, di-, or trimethylated state, thereby extending the indexing potential of this particular modification. Here, we examine all possible methylation states for histone H3 lysine 9 (H3-K9) and lysine 27 (H3-K27) in mammalian chromatin. Using highly specific antibodies together with quantitative mass spectrometry, we demonstrate that pericentric heterochromatin is selectively enriched for H3-K27 monomethylation and H3-K9 trimethylation. This heterochromatic methylation profile is dependent on the Suv39h histone methyltransferases (HMTases) but independent of the euchromatic G9a HMTase. In Suv39h double null cells, pericentric heterochromatin is converted to alternative methylation imprints and accumulates H3-K27 trimethylation and H3-K9 monomethylation. Our data underscore the selective presence of distinct histone lysine methylation states in partitioning chromosomal subdomains but also reveal a surprising plasticity in propagating methylation patterns in eukaryotic chromatin.

Amino Acid Sequence↗
PubMed2005

Fully grown mouse oocyte contains transcription inhibiting activity which acts through histone deacetylation.

Mouse ovarian oocytes remain transcriptionally active during the entire period of oocyte growth. In the fully grown antral oocytes, RNA synthesis is terminated before initiation of maturation. The mechanism involved in this process remains unknown. It was proposed that some signals provided by companion granulosa cells, and accumulating in the cytoplasm of the oocyte, play a role in the termination of RNA synthesis. It seems possible that under influence of these signals, the oocyte cytoplasm becomes transcriptionally nonpermissive. In the present study, transcriptionally active, single blastomeres of the 8-cell mouse embryo were fused with nontranscribing fully grown oocytes, and RNA synthesis was analyzed in the resulting hybrids. We show that after 27 hr of culture of hybrid cells, transcription in the blastomere nuclei was finally silenced. This process occurs without nuclear envelope breakdown and is accompanied by progressive condensation of the chromatin in the blastomere nuclei. We show also the involvement of core histone deacetylation in the modification of chromatin configuration and termination of RNA synthesis in the blastomere nuclei.

Animals↗
PubMed2026

Epigenetic and Transcriptional Regulatory Networks Underlying Psoriasis Pathogenesis.

Psoriasis is a chronic, immune-mediated dermatologic disorder characterized by the hyperproliferation of keratinocytes and dysregulated immune signaling. Although genome-wide association studies have identified susceptibility loci, the multifactorial nature of the disease underlines the importance of nongenetic regulatory mechanisms. Among these epigenetic modifications are those that critically link genetic predisposition with environmental stimuli. This review offers an in-depth overview of the current insights into the role of epigenetic regulation in the pathophysiology of psoriasis. Key mechanisms, including aberrant DNA methylation, histone post-translational modifications (eg, H3K27ac, H3K4me3), and dysregulated noncoding RNAs, are discussed in the context of inflammatory signaling and immune cell function. This review also explores how environmental factors such as UV radiation and air pollution induce the epigenetic reprogramming that perpetuates the proinflammatory state. Furthermore, it highlights the translational potential of targeting epigenetic regulators and epigenome-editing technologies, including clustered regularly interspaced short palindromic repeats (CRISPR) fusion systems, as precision therapeutic strategies. In parallel, advances in single-cell epigenomics, spatial transcriptomics, and the profiling of circulating biomarkers offer novel diagnostic tools. Despite advances, challenges persist, including the limited predictive value of preclinical models and variable epigenetic profiles. Positioning epigenetics as the bridge between genetic risk, environmental triggers, and therapeutic advances, this review presents a framework for precision medicine in psoriasis.

Humans↗
PubMed1981

Histone synthesis in preimplantation mouse embryos.

The synthesis of histones by preimplantation mouse embryos was examined by electrophoresis of [3H]-lysine-labeled acid extracts of cleavage stage embryos. Histones were synthesized by fertilized zygotes, two-cell, eight-cell, and morula stage embryos. Their identity was confirmed by coextraction and coelectrophoresis in a number of systems and differential labeling with [3H]-tryptophan. There was evidence of post-translational modifications of the embryonic histones. The estimated histone synthetic rate was sufficient to provide the chromatin requirements of cleavage division as related to DNA synthesis. The results are discussed in relation to coordination of histone and DNA synthesis in the preimplantation embryo.

Animals↗
PubMed2003

Histone deacetylase in carcinogenesis and its inhibitors as anti-cancer agents.

The acetylation state of histone is reversibly regulated by histone acetyltransferase (HAT) and deacetylase (HDAC). An imbalance of this reaction leads to an aberrant behavior of the cells in morphology, cell cycle, differentiation, and carcinogenesis. Recently, these key enzymes in the gene expression were cloned. They revealed a broad use of this modification, not only in histone, but also other proteins that involved transcription, nuclear transport, and cytoskeleton. These results suggest that HAT/HDAC takes charge of multiple-functions in the cell, not just the gene expression. HDAC is especially known to play an important role in carcinogenesis. The enzyme has been considered a target molecule for cancer therapy. The inhibition of HDAC activity by a specific inhibitor induces growth arrest, differentiation, and apoptosis of transformed or several cancer cells. Some of these inhibitors are in a clinical trial at phase I or phase II. The discovery and development of specific HDAC inhibitors are helpful for cancer therapy, and decipher the molecular mode of action for HDAC.

Acetyltransferases↗
PubMed2005

Assembly of variant histones into chromatin.

Chromatin can be differentiated by the deposition of variant histones at centromeres, active genes, and silent loci. Variant histones are assembled into nucleosomes in a replication-independent manner, in contrast to assembly of bulk chromatin that is coupled to replication. Recent in vitro studies have provided the first glimpses of protein machines dedicated to building and replacing alternative nucleosomes. They deposit variant H2A and H3 histones and are targeted to particular functional sites in the genome. Differences between variant and canonical histones can have profound consequences, either for delivery of the histones to sites of assembly or for their function after incorporation into chromatin. Recent studies have also revealed connections between assembly of variant nucleosomes, chromatin remodeling, and histone post-translational modification. Taken together, these findings indicate that chromosome architecture can be highly dynamic at the most fundamental level, with epigenetic consequences.

Animals↗
PubMed2003

Histone H1 and the dynamic regulation of chromatin function.

Eukaryotic DNA is organized in a complex structure called chromatin. Although a primary function of chromatin is compaction of DNA, this must done such that the underlying DNA is potentially accessible to factor-mediated regulatory responses. Chromatin structure clearly plays a dominant role in regulating much of eukaryotic transcription. The demonstration that reversible covalent modification of the core histones contribute to transcriptional activation and repression by altering chromatin structure and the identification of numerous ATP-dependent chromatin remodeling enzymes provide strong support for this view. Chromatin is much more dynamic than was previously thought and regulation of the dynamic properties of chromatin is a key aspect of gene regulation. This review will focus on recent attempts to elucidate the specific contribution of histone H1 to chromatin-mediated regulation of gene expression.

Animals↗
PubMedDate not supplied

[Adenylate cyclase system and structural modifications of nuclear proteins in organisms radioprotection].

The paper deals with modern ideas of ways and mechanisms for realization of the radioprotector antiradiation effect. The data on the effect of biogenic amines (serotonin in particular) and radiation on the cAMP system are analyzed. It is shown that one of the most important mechanisms of the radioprotective effect is realized by changing the levels of histones and nonhistone proteins modifications through the adenylate cyclase system which leads to regulation of the chromatin template activity.

Adenylyl Cyclases↗
PubMed2005

Chromatin modifier enzymes, the histone code and cancer.

In all organisms, cell proliferation is orchestrated by coordinated patterns of gene expression. Transcription results from the activity of the RNA polymerase machinery and depends on the ability of transcription activators and repressors to access chromatin at specific promoters. During the last decades, increasing evidence supports aberrant transcription regulation as contributing to the development of human cancers. In fact, transcription regulatory proteins are often identified in oncogenic chromosomal rearrangements and are overexpressed in a variety of malignancies. Most transcription regulators are large proteins, containing multiple structural and functional domains some with enzymatic activity. These activities modify the structure of the chromatin, occluding certain DNA regions and exposing others for interaction with the transcription machinery. Thus, chromatin modifiers represent an additional level of transcription regulation. In this review we focus on several families of transcription activators and repressors that catalyse histone post-translational modifications (acetylation, methylation, phosphorylation, ubiquitination and SUMOylation); and how these enzymatic activities might alter the correct cell proliferation program, leading to cancer.

Acetylation↗
PubMedDate not supplied

[Tyrosine residues in histones. Kinetics of histones F1 and F2A1 nitration by tetranitromethane].

The kinetics of nitration of tyrosine residues in histones F1 and F2a1 by tetranitromethane has been investigated. At low ionic strength and 30-fold molar excess of nitrating agent the nitration reaction results in fast modification of all tyrosine residues in both histones. At the same time the rates of modification of different tyrosine residues in histone F2a1 are not identical and markedly exceed the rate of N-Ac-OEt-Tyr nitration in a model system. The increase of reaction mixture ionic strength causes an increase of modification rates. The differential UV-absorption spectra of histone F1 obtained by temperature perturbation show an abnormal positive characteristic maximum at 286.8 nm. Analysis of the dependence of nitration rates of tyrosine residues in histones in saline solutions upon the ionic strength and of difference UV-absorption spectra of histones leads to a conclusion that there are specific interactions of definite parts of histone polypeptide chains. These interactions may arise from aggregation of histone molecules.

Animals↗
PubMed2002

Analysis of histone acetyltransferase and histone deacetylase families of Arabidopsis thaliana suggests functional diversification of chromatin modification among multicellular eukaryotes.

Sequence similarity and profile searching tools were used to analyze the genome sequences of Arabidopsis thaliana, Saccharomyces cerevisiae, Schizosaccharomyces pombe, Caenorhabditis elegans and Drosophila melanogaster for genes encoding three families of histone deacetylase (HDAC) proteins and three families of histone acetyltransferase (HAT) proteins. Plants, animals and fungi were found to have a single member of each of three subfamilies of the GNAT family of HATs, suggesting conservation of these functions. However, major differences were found with respect to sizes of gene families and multi-domain protein structures within other families of HATs and HDACs, indicating substantial evolutionary diversification. Phylogenetic analysis identified a new class of HDACs within the RPD3/HDA1 family that is represented only in plants and animals. A similar analysis of the plant-specific HD2 family of HDACs suggests a duplication event early in dicot evolution, followed by further diversification in the lineage leading to Arabidopsis. Of three major classes of SIR2-type HDACs that are found in animals, fungi have representatives only in one class, whereas plants have representatives only in the other two. Plants possess five CREB-binding protein (CBP)-type HATs compared with one to two in animals and none in fungi. Domain and phylogenetic analyses of the CBP family proteins showed that this family has evolved three distinct types of CBPs in plants. The domain architecture of CBP and TAF(II)250 families of HATs show significant differences between plants and animals, most notably with respect to bromodomain occurrence and their number. Bromodomain-containing proteins in Arabidopsis differ strikingly from animal bromodomain proteins with respect to the numbers of bromodomains and the other types of domains that are present. The substantial diversification of HATs and HDACs that has occurred since the divergence of plants, animals and fungi suggests a surprising degree of evolutionary plasticity and functional diversification in these core chromatin components.

Acetyltransferases↗
PubMed2004

The C-terminal domain is the primary determinant of histone H1 binding to chromatin in vivo.

We have used a combination of kinetic measurements and targeted mutations to show that the C-terminal domain is required for high-affinity binding of histone H1 to chromatin, and phosphorylations can disrupt binding by affecting the secondary structure of the C terminus. By measuring the fluorescence recovery after photo-bleaching profiles of green fluorescent protein-histone H1 proteins in living cells, we find that the deletion of the N terminus only modestly reduces binding affinity. Deletion of the C terminus, however, almost completely eliminates histone H1.1 binding. Specific mutations of the C-terminal domain identified Thr-152 and Ser-183 as novel regulatory switches that control the binding of histone H1.1 in vivo. It is remarkable that the single amino acid substitution of Thr-152 with glutamic acid was almost as effective as the truncation of the C terminus to amino acid 151 in destabilizing histone H1.1 binding in vivo. We found that modifications to the C terminus can affect histone H1 binding dramatically but have little or no influence on the charge distribution or the overall net charge of this domain. A comparison of individual point mutations and deletion mutants, when reviewed collectively, cannot be reconciled with simple charge-dependent mechanisms of C-terminal domain function of linker histones.

Alanine↗
PubMed2006

Leaving a mark: the many footprints of the elongating RNA polymerase II.

The elongation phase of transcription by RNA polymerase II involves a complex choreography of events besides the polymerization of RNA. In addition to coordinating the processing of the nascent transcript, elongating RNA polymerase II recruits histone methyltransferases to methylate lysines 4 and 36 of histone H3 in nucleosomes in the body of actively transcribed genes. Methylation at these sites is genetically implicated in marking actively transcribed genes. Recent studies link transcriptional elongation by RNA polymerase II to H3K9 methylation and the recruitment of the HP1 family protein HP1gamma. These findings expand the role for RNA polymerase II elongation in targeting chromatin modifications to include a histone methyl mark more commonly associated with gene silencing.

Animals↗
PubMed2006

A novel histone exchange factor, protein phosphatase 2Cgamma, mediates the exchange and dephosphorylation of H2A-H2B.

In eukaryotic nuclei, DNA is wrapped around a protein octamer composed of the core histones H2A, H2B, H3, and H4, forming nucleosomes as the fundamental units of chromatin. The modification and deposition of specific histone variants play key roles in chromatin function. In this study, we established an in vitro system based on permeabilized cells that allows the assembly and exchange of histones in situ. H2A and H2B, each tagged with green fluorescent protein (GFP), are incorporated into euchromatin by exchange independently of DNA replication, and H3.1-GFP is assembled into replicated chromatin, as found in living cells. By purifying the cellular factors that assist in the incorporation of H2A-H2B, we identified protein phosphatase (PP) 2C gamma subtype (PP2Cgamma/PPM1G) as a histone chaperone that binds to and dephosphorylates H2A-H2B. The disruption of PP2Cgamma in chicken DT40 cells increased the sensitivity to caffeine, a reagent that disturbs DNA replication and damage checkpoints, suggesting the involvement of PP2Cgamma-mediated histone dephosphorylation and exchange in damage response or checkpoint recovery in higher eukaryotes.

Amanitins↗
PubMed2002

Structure of HP1 chromodomain bound to a lysine 9-methylated histone H3 tail.

The chromodomain of the HP1 family of proteins recognizes histone tails with specifically methylated lysines. Here, we present structural, energetic, and mutational analyses of the complex between the Drosophila HP1 chromodomain and the histone H3 tail with a methyllysine at residue 9, a modification associated with epigenetic silencing. The histone tail inserts as a beta strand, completing the beta-sandwich architecture of the chromodomain. The methylammonium group is caged by three aromatic side chains, whereas adjacent residues form discerning contacts with one face of the chromodomain. Comparison of dimethyl- and trimethyllysine-containing complexes suggests a role for cation-pi and van der Waals interactions, with trimethylation slightly improving the binding affinity.

Amino Acid Motifs↗
PubMed1987

Histone proteins in fetal and adult human retinas.

The DNA-binding histone proteins from the human retina are described for the first time. Retinas were obtained from male and female donors ranging in age from 11 to 72 years old. Retinas from two human fetuses at approximately four months of gestation were also examined for their histone content. Histones extracted from purified nuclei were separated and analyzed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). Eight histone fractions were identified in all retinal samples, and were quantified by scanning transmittance densitometry. These fractions included three subfractions of linker histones (H1a, H1b, H1(0)), four nucleosomal core histones (H2A, H2B, H3, H4), and the modified core histone, A24 (uH2A), comprised of H2A covalently bound to the non-histone protein, ubiquitin. When fetal and adult retinal histones were compared, the relative amounts of the linker histone subfractions proved to be different. In the adult retinas, H1a diminished in amount whereas H1b and H1(0) were increased. No alterations were detected in the core histones. The developmental changes in linker histones may be related to modifications of chromatin compaction which accompany cell differentiation. Species differences in the pattern of linker histones were detected when the nuclear proteins of human and mouse retinas were compared. Non-histone nuclear proteins are more abundant in the adult human retina than in the mouse retina or the fetal human retina.

Adult↗
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↗
PubMed1990

Organic osmotic effectors and chromatin structure.

Organic amino compounds (taurine, glycine) and polyols (mannitol, sorbitol) are used as osmotic effectors by most animal cells, particularly by some marine invertebrates, but also to a limit extent by mammalian cells. Using physico-chemical techniques (circular dichroism, thermal denaturation, solubility, electrophoresis and electric linear dichroism), we demonstrated that some of these effectors prevent chromatin aggregation, without histone release. The influence of glycine on chromatin aggregation, dissociation and reconstitution was thoroughly investigated. Glycine at 2 M concentration does not in itself induce chromatin dissociation; it does hinder salt-induced histone dissociation from chromatin (especially at 1.2 M NaCl) but does not impede chromatin reconstitution. Several hypothesis may be put forward to explain the action of these effectors: (i) a modulation of histone conformation; (ii) a modification of fractional DNA charge, either directly by the zwitterions (glycine, taurine) or indirectly by alteration of cations counterions hydration. The physiological relevance of our experiments is also discussed.

Animals↗