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At least 145 records · Page 8Linked to original sources
PubMed2003

Chromatin of the Barr body: histone and non-histone proteins associated with or excluded from the inactive X chromosome.

The Barr body has long been recognized as the cytological manifestation of the inactive X chromosome (Xi) in interphase nuclei. Despite being known for over 50 years, relatively few components of the Barr body have been identified. In this study, we have screened over 30 histone variants, modified histones and non-histone proteins for their association with or exclusion from the Barr body. We demonstrate that, similar to the histone variant macroH2A, heterochromatin protein-1 (HP1), histone H1 and the high mobility group protein HMG-I/Y are elevated at the territory of the Xi in interphase in human cell lines, but only when the Xi chromatin is heteropycnotic, implicating each as a component of the Barr body. Surprisingly, however, virtually all other candidate proteins involved in establishing heterochromatin and gene silencing are notably absent from the Barr body despite being localized generally elsewhere throughout the nucleus, indicating that the Barr body represents a discrete subnuclear compartment that is not freely accessible to most chromatin proteins. A similar dichotomous pattern of association or exclusion describes the spatial relationship of a number of specific histone methylation patterns in relation to the Barr body. Notably, though, several methylated forms of histone H3 that are deficient in Xi chromatin generally are present at a region near the macrosatellite repeat DXZ4, as are the chromatin proteins CTCF and SAP30, indicating a distinctive chromatin state in this region of the Xi. Taken together, our data imply that the Xi adopts a distinct chromatin configuration in interphase nuclei and are consistent with a mechanism by which HP1, through histone H3 lysine-9 methylation, recognizes and assists in maintaining heterochromatin and gene silencing at the human Xi.

CCCTC-Binding Factor↗
PubMed2002

Functional and physical interaction between the histone methyl transferase Suv39H1 and histone deacetylases.

The histone methyl transferase Suv39H1 is involved in silencing by pericentric heterochromatin. It specifically methylates K9 of histone H3, thereby creating a high affinity binding site for HP1 proteins. We and others have shown recently that it is also involved in transcriptional repression by the retinoblastoma protein Rb. Strikingly, both HP1 localisation and repression by Rb also require, at least in part, histone deacetylases. We found here that repression of a heterologous promoter by Suv39H1 is dependent on histone deacetylase activity. However, the enzymatic activity of Suv39H1 is not required, since the N-terminal part is by itself a transcriptional repression domain. Coimmunoprecipitation experiments indicated that Suv39H1 can physically interact with HDAC1, -2 and -3, therefore suggesting that transcriptional repression by Suv39H1 could be the consequence of histone deacetylases recruitment. Consistent with this interpretation, the N-terminal transcriptional repression domain of Suv39H1 bound the so-called 'core histone deacetylase complex', composed of HDAC1, HDAC2 and the Rb-associated proteins RbAp48 and RbAp46. Taken together, our results suggest that a complex containing both the Suv39H1 histone methyl transferase and histone deacetylases could be involved in heterochromatin silencing or transcriptional repression by Rb.

Binding Sites↗
PubMed2003

Histone deacetylases: unique players in shaping the epigenetic histone code.

The epigenome is defined by DNA methylation patterns and the associated posttranslational modifications of histones. This histone code determines the expression status of individual genes dependent upon their localization on the chromatin. The silencing of gene expression is associated with deacetylated histones, which are often found to be associated with regions of DNA methylation as well as methylation at the lysine 4 residue of histone 3. In contrast, the activation of gene expression is associated with acetylated histones and methylation at the lysine 9 residue of histone 3. The histone deactylases play a major role in keeping the balance between the acetylated and deacetylated states of chromatin. Histone deacetylases (HDACs) are divided into three classes: class I HDACs (HDACs 1, 2, 3, and 8) are similar to the yeast RPD3 protein and localize to the nucleus; class II HDACs (HDACs 4, 5, 6, 7, 9, and 10) are homologous to the yeast HDA1 protein and are found in both the nucleus and cytoplasm; and class III HDACs form a structurally distinct class of NAD-dependent enzymes that are similar to the yeast SIR2 proteins. Since inappropriate silencing of critical genes can result in one or both hits of tumor suppressor gene (TSG) inactivation in cancer, theoretically the reactivation of affected TSGs could have an enormous therapeutic value in preventing and treating cancer. Indeed, several HDAC inhibitors are currently being developed and tested for their potency in cancer chemotherapy. Importantly, these agents are also potentially applicable to chemoprevention if their toxicity can be minimized. Despite the toxic side effects and lack of specificity of some of the inhibitors, progress is being made. With the elucidation of the structures, functions and modes of action of HDACs, finding agents that may be targeted to specific HDACs and potentially reactivate expression of only a defined set of affected genes in cancer will be more attainable.

Acetylation↗
PubMed2006

Dynamic changes in chromatin acetylation and the expression of histone acetyltransferases and histone deacetylases regulate the SM22alpha transcription in response to Smad3-mediated TGFbeta1 signaling.

TGFbeta1 plays critical roles in stimulating smooth muscle gene transcription during myofibroblast and smooth muscle cell (SMC) differentiation. Increasing evidence demonstrates that histone modification plays important roles in regulating gene transcription. Here, we investigated the effect of changes in the expression of histone acetyltransferases (HAT) or histone deacetylases (HDAC) on TGFbeta1-induced SM22 promoter activities. We found that overexpressing HAT proteins such as p300 and CBP enhances TGFbeta1-induced SM22 promoter activities; conversely, overexpressing HAT inhibitor such as Twist1 (but not Twist2/Dermo-1) and E1A suppresses this effect of TGFbeta1. We also found that TSA, a HDAC inhibitor that stimulates histone acetylation of the SM22alpha locus, further enhances the transactivational activity of Smad2, Smad3 and Smad4, and relieves the inhibitory effect of Smad6, Smad7, and the dominant negative mutants of Smads. TGFbeta1 also stimulates the association of Smad3 (a potent transactivator for the SM22 promoter) and p300 by co-immunoprecipitation assay. In contrast, overexpressing HDAC 1-6 inhibits TGFbeta1-induced as well as Smad3 and myocardin-activated SM22 promoter. Moreover, chromatin immunoprecipitation (ChIP) assays show that TGFbeta1 induces histone acetylation at the SM22alpha locus. This study demonstrates that the balance of HAT and HDAC expression affects TGFbeta1-induced SM22alpha transcription; TGFbeta1-induced SM22alpha transcription is accompanied by histone hyperacetylation at the SM22alpha locus. This study provides the first evidence showing that histone hyperacetylation of the SM22 promoter is a target of TGFbeta1 signaling, suggesting that modulation of histone acetylation is involved in the molecular mechanisms of TGFbeta1-regulated SMC gene transcription.

Acetylation↗
PubMed1997

Turnover of histone acetyl groups during sea urchin early development is not required for histone, heat shock and actin gene transcription.

Histone acetylation is an extremely complex, reversible and specific process. In order to evaluate the importance of this modification for gene expression during sea urchin development, acetyl group turnover of histone lysine residues was blocked by sodium butyrate. The continuous presence of 15 Mm sodium butyrate in the incubation medium from the onset of development blocked gastrulation and resulted in chromatin containing hyperacetylated histone molecules in amounts usually not found in nature. At the mesenchyme blastula stage, the expression of the early histone genes was shut off and the expression of the late genes was switched on both in control and sodium butyrate-treated embryos. Investigation of the early histone gene chromatin structure in butyrate-treated embryos revealed a random distribution of nucleosomes when the genes were transcriptionally active as compared to regular nucleosomal packaging when genes were inactive. These changes in chromatin structure during development mimicked the chromatin structural transition of the early histone genes in control embryos. In addition, the ability of heat shock genes to be induced at elevated temperature and repressed at normal temperature was unaffected in butyrate treatment of embryos. Finally, the developmental profiles of the cytoskeletal CyIIIa actin gene expression in control and butyrate-treated embryos were very similar. The data presented suggest that turnover of histone acetyl groups and the overall level of histone acetylation are not determining factors in the up and down regulation of a number of genes during early development of sea urchin.

Acetylation↗
PubMed2003

Molecular basis for Gcn5/PCAF histone acetyltransferase selectivity for histone and nonhistone substrates.

Histone acetyltransferase (HAT) proteins often exhibit a high degree of specificity for lysine-bearing protein substrates. We have previously reported on the structure of the Tetrahymena Gcn5 HAT protein (tGcn5) bound to its preferred histone H3 substrate, revealing the mode of substrate binding by the Gcn5/PCAF family of HAT proteins. Interestingly, the Gcn5/PCAF HAT family has a remarkable ability to acetylate lysine residues within diverse cognate sites such as those found around lysines 14, 8, and 320 of histones H3, H4, and p53, respectively. To investigate the molecular basis for this, we now report on the crystal structures of tGcn5 bound to 19-residue histone H4 and p53 peptides. A comparison of these structures with tGcn5 bound to histone H3 reveals that the Gcn5/PCAF HATs can accommodate divergent substrates by utilizing analogous interactions with the lysine target and two C-terminal residues with a related chemical nature, suggesting that these interactions play a general role in Gcn5/PCAF substrate binding selectivity. In contrast, while the histone H3 complex shows extensive interactions with tGcn5 and peptide residues N-terminal to the target lysine, the corresponding residues in histone H4 and p53 are disordered, suggesting that the N-terminal substrate region plays an important role in the enhanced affinity of the Gcn5/PCAF HAT proteins for histone H3. Together, these studies provide a framework for understanding the substrate selectivity of HAT proteins.

Acetyltransferases↗
PubMed1979

Does high-mobility-group non-histone protein HMG 1 interact specifically with histone H1 subfractions?

The interaction of the non-histone chromosomal protein HMG (high-mobility group) 1 with histone H1 subfractions was investigated by equilibrium sedimentation and n.m.r. sectroscopy. In contrast with a previous report [Smerdon & Isenberg (1976) Biochemistry 15, 4242--4247], it was found, by using equilibrium-sedimentation analysis, that protein HMG 1 binds to all three histone H1 subfractions CTL1, CTL2, and CTL3, arguing against there being a specific interaction between protein HMG 1 and only two of the subfractions, CTL1 and CTL2. Raising the ionic strength of the solutions prevents binding of protein HMG 1 to total histone H1 and the three subfractions, suggesting that the binding in vitro is simply a non-specific ionic interaction between acidic regions of the non-histone protein and the basic regions of the histone. Protein HMG 1 binds to histone H5 also, supporting this view. The above conclusions are supported by n.m.r. studies of protein HMG 1/histone H1 subfraction mixtures. When the two proteins were mixed, there was little perturbation of the n.m.r. spectra and there was no evidence for specific interaction of protein HMG 1 with any of the subfractions. It therefore remains an open question as to whether protein HMG 1 and histone H1 are complexed together in chromatin.

Centrifugation, Density Gradient↗
PubMed1991

Possible role of histone acetylation and histone H1(0) replacement for the initiation of replication in regenerating rat liver.

The role of histone acetylation and DNA synthesis has been investigated extensively in the regenerating rat liver system in the presence and absence of the cyclophosphamide derivative mafosfamide. We demonstrate a mafosfamide-induced inhibition of maximum histone acetyltransferase activity followed by a second elevation of enzyme activity and an accompanying total suppression of DNA synthesis for 7-8 h. The maximum of histone acetyltransferase activity, in parallel with an elevated acetylation in vivo, the consecutive replacement of histone H1(0) amd initiation of replication occur sequentially in the presence and absence of mafosfamide, but with a temporary delay of 7-8 h. Our data indicate that modifications of histone acetyltransferase (EC 2.3.1.48) activity do not significantly influence the acetylation patterns of histones H3 and H4. The mafosfamide-induced change of histone acetyltransferase activity and acetylation in vivo, the shift of histone H1(0) exchange and the consecutive transition of initiation of replication suggest that these three events might be functionally related.

Acetylation↗
PubMed1983

Antibodies to histones in systemic lupus erythematosus: localization of prominent autoantigens on histones H1 and H2B.

By the technique of immunoblotting we have assessed the ability of sera from 24 patients with systemic lupus erythematosus to bind nuclear proteins. Of the 11 patients who had antibodies to histones, 10 had antibodies to histone H1 and 9 of these also had antibodies to histone H2B. Antibodies to the other histones (H2A, H3, and H4) were less apparent. Five of the 11 patients (and two others in the remainder of the sample of 24) also had antibodies to a small number of nonhistone proteins that are probably components of ribonucleoprotein particles, but there was no obvious correlation between the presence of antihistone antibodies and the known antiribonucleoprotein activity of these sera. Separate determinants on H1 and H2B were demonstrated by immunoblotting with affinity-purified anti-H1 and anti-H2B antibodies derived from serum that showed both specificities. The localization of the determinants within the histone polypeptide chains was shown by immunoblotting with large fragments produced by specific proteolytic or chemical cleavage of the histones. The strongest determinant on H1 was located within the COOH-terminal half, with a weaker determinant being present within the NH2-terminal half; the H2B determinant(s) was located entirely within the NH2-terminal half of the molecule. The selectivity with which the antihistone antibodies in systemic lupus erythematosus are produced against the more exposed histones in the nucleosome (and perhaps against the most exposed regions of these histones) is consistent with the involvement of intact chromatin structures as immunogens in this disease.

Antigens↗
PubMed2005

The role of histone H2Av variant replacement and histone H4 acetylation in the establishment of Drosophila heterochromatin.

Activation and repression of transcription in eukaryotes involve changes in the chromatin fiber that can be accomplished by covalent modification of the histone tails or the replacement of the canonical histones with other variants. Here we show that the histone H2A variant of Drosophila melanogaster, H2Av, localizes to the centromeric heterochromatin, and it is recruited to an ectopic heterochromatin site formed by a transgene array. His2Av behaves genetically as a PcG gene and mutations in His2Av suppress position effect variegation (PEV), suggesting that this histone variant is required for euchromatic silencing and heterochromatin formation. His2Av mutants show reduced acetylation of histone H4 at Lys 12, decreased methylation of histone H3 at Lys 9, and a reduction in HP1 recruitment to the centromeric region. H2Av accumulation or histone H4 Lys 12 acetylation is not affected by mutations in Su(var)3-9 or Su(var)2-5. The results suggest an ordered cascade of events leading to the establishment of heterochromatin and requiring the recruitment of the histone H2Av variant followed by H4 Lys 12 acetylation as necessary steps before H3 Lys 9 methylation and HP1 recruitment can take place.

Acetylation↗
PubMed1987

Histone synthesis during the cell cycle of Physarum polycephalum. Synthesis of different histone species is not under a common regulatory control.

The synthesis of histones and nonhistone nuclear proteins was studied during the naturally synchronous cell cycle of Physarum polycephalum. Contrary to the commonly accepted idea of a tight coupling of histone biosynthesis and DNA replication during the somatic cell cycle we found that 40% of total histone synthesis takes place in the G2 period in the complete absence of DNA synthesis. The core histones exhibit a maximum of synthesis during S-phase. The synthesis of histones H2A and H2B continues during the G2 period, but synthesis of H4 and H3 is restricted to the S-phase of the cell cycle. Experiments with hydroxyurea demonstrated that the synthesis of H4 and H3 is completely dependent on unperturbed DNA synthesis, whereas synthesis of H2A and H2B is independent from DNA synthesis during the entire cell cycle. This implicates significant differences between the arginine-rich histones H4 and H3 and the moderately lysine-rich histones H2A and H2B with respect to the control mechanisms of their synthesis, the metabolic stability, and the function for chromatin structure. The nonhistone nuclear proteins are synthesized throughout the cell cycle with a broad maximum in the early G2 period. The cell cycle pattern of synthesis of H1 rather resembles the pattern of the nonhistone proteins than of core histones.

Cell Cycle↗