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PubMed1983

Covalent modifications of chromosomal proteins during aging.

Covalent modifications of proteins introduce negative or positive charges into the molecules and thereby cause alterations in the ionic interactions of protein-protein or DNA-protein complexes. Whereas modifications of histones largely affect the organization of chromatin, those of non-histone proteins are believed to be involved in the expression of genes. These modifications during aging have been reviewed here. The available data suggest that the extent of covalent modifications of histones and non-histone chromosomal (NHC) proteins change during aging and such modifications may have an important role in the differential expression of genes at different phases of life span of an organism.

Acetylation↗

PubMed2002

Structure of the HP1 chromodomain bound to histone H3 methylated at lysine 9.

Specific modifications to histones are essential epigenetic markers---heritable changes in gene expression that do not affect the DNA sequence. Methylation of lysine 9 in histone H3 is recognized by heterochromatin protein 1 (HP1), which directs the binding of other proteins to control chromatin structure and gene expression. Here we show that HP1 uses an induced-fit mechanism for recognition of this modification, as revealed by the structure of its chromodomain bound to a histone H3 peptide dimethylated at Nzeta of lysine 9. The binding pocket for the N-methyl groups is provided by three aromatic side chains, Tyr21, Trp42 and Phe45, which reside in two regions that become ordered on binding of the peptide. The side chain of Lys9 is almost fully extended and surrounded by residues that are conserved in many other chromodomains. The QTAR peptide sequence preceding Lys9 makes most of the additional interactions with the chromodomain, with HP1 residues Val23, Leu40, Trp42, Leu58 and Cys60 appearing to be a major determinant of specificity by binding the key buried Ala7. These findings predict which other chromodomains will bind methylated proteins and suggest a motif that they recognize.

Amino Acid Sequence↗

PubMed1990

[Modulation of the binding characteristics of thyroid hormone receptors by the chemical modification of non-histone nuclear proteins].

Modulation of binding characteristics of thyroid hormone receptors induced by chemical modification of nonhistone proteins is described. At nuclear level, the biological response to thyroid hormones is determined by the formation of hormone-receptor complexes which act as the initiation factor of hormone action. The combination of common biochemical separation methods allows only partial purification of the thyroid hormone receptors. The product of the c-erb-A genes carries the sequence representing the thyroid hormone receptor. At present neither the structure nor the exact amino acid sequence of the specific binding site for the thyroid hormone at the receptor molecule is known. The formation of the biologically active thyroid hormone-receptor complex was found to require the preservation of at least one of the 19 nucleophilic imidazole groups of the histidyl residues of the 3,5,3'-triidothyronine receptor.

Animals↗

PubMed2003

Alp13, an MRG family protein, is a component of fission yeast Clr6 histone deacetylase required for genomic integrity.

The post-translational modifications of histones are key to the modulation of chromatin structure. Distinct patterns of modifications established by histone-modifying enzymes control diverse chromosomal processes. Here, we report the purification and molecular characterization of the fission yeast Clr6 histone deacetyl ase involved in higher order chromatin assembly. We show that a chromodomain protein Alp13, which belongs to the conserved MRG protein family linked to cellular senescence in humans, is associated with Clr6. In addition, Clr6 interacts with homologs of the mammalian transcriptional co-repressors Sin3, Pst1 and Pst2, and a WD40 repeat-containing protein, Prw1. Alp13, Pst2 and Prw1 form a stable complex with Clr6 in the nucleus. Deletion of any of these factors causes progressive loss of viability and sensitivity to DNA-damaging agents, and impairs condensation/resolution of chromosomes during mitosis. This is accompanied by hyperacetylation of histones and a reduction in histone H3 Ser10 phosphorylation, which correlates with chromosome condensation during mitosis. These results link the MRG family protein Alp13 to histone deacetylation, and suggest that Clr6 and its associated factors are essential for fundamental chromosomal events.

Acetylation↗

PubMed2026

Epigenetic regulation of kidney development.

The methylation or demethylation of genomic DNA at specific locations and the diverse array of post-translational modifications of histones associated with genomic DNA are collectively known as epigenetic modifications, so-called because they affect chromatin structure but do not affect the actual DNA sequence of the genome. Nevertheless, post-translational modifications of histones, including methylation, acetylation, phosphorylation and ubiquitination, as well as the methylation and subsequent de-methylation of genomic DNA, can profoundly affect gene expression. Nowhere has the study of epigenetically regulated gene expression had such impact as on our understanding of organism development. In the developing kidney, epigenetic-based regulation affects the cell fate decisions of stem-like nephron progenitor cells (NPCs). Changes in chromatin accessibility at the loci of genes associated with NPC self-renewal and nephron differentiation - in part driven by transcription factors known to regulate kidney development - affect the differentiation of NPCs into precursors of the nephron such as the pretubular aggregate and renal vesicle, and the subsequent differentiation of various segments of the mature nephron. Epigenetic mechanisms also contribute to the process of NPC ageing and the cessation of nephrogenesis, with consequences for nephron endowment and kidney function.

Epigenesis, Genetic↗

PubMed2025

Chromatin state dynamics of autosomes and the B chromosome during spermatogenesis in Pseudococcus viburni.

The mealybug Pseudococcus viburni is a plant-feeding insect with a non-Mendelian genetic system known as paternal genome elimination (PGE). In PGE, males eliminate their paternally inherited chromosomes during meiosis, transmitting only the maternal genome to the next generation. This involves genome-wide imprinting, where paternal chromosomes are heterochromatinised in embryogenesis and throughout adulthood. In this species, a non-essential B chromosome can escape paternal genome elimination, thereby enhancing its transmission rate to the next generation. Previous studies show that the B chromosome escapes elimination by changing its chromatin compaction during meiosis to resemble that of maternal chromosomes. Although the exact mechanism underlying this change is poorly understood. Here we investigated histone methylation and acetylation modifications, as well as the Heterochromatin Protein 1 (HP1), to characterise differences between maternal, paternal and B chromosomes during male meiosis of P. viburni. Maternal and paternal chromosomes show distinct histone modification patterns, with marks associated with euchromatin present on maternal chromosomes and marks associated with heterochromatin present on paternal chromosomes. We then identified key histone modification changes that coincide with chromatin remodelling of the B chromosome, which allows it to segregate with maternal chromosomes. In addition, we showed that these chromatin modifications occur regardless of the parental origin of the B chromosome. Overall, our findings support the role of histone modifications for proper chromosome segregation during meiosis in mealybugs and provide insight into the mechanisms by which the B chromosome exploits PGE for its preferential transmission.

Animals↗

PubMed2002

The elusive structural role of ubiquitinated histones.

It is increasingly apparent that histone posttranslational modifications are important in chromatin structure and dynamics. However, histone ubiquitination has received little attention. Histones H1, H3, H2A, and H2B can be ubiquitinated in vivo, but the most prevalent are uH2A and uH2B. The size of this modification suggests some sort of structural impact. Physiological observations suggest that ubiquitinated histones may have multiple functions and structural effects. Ubiquitinated histones have been correlated with transcriptionally active DNA, implying that it may prevent chromatin folding or help maintain an open conformation. Also, in some organisms during spermiogenesis, a process involving extensive chromatin remodeling, uH2A levels increase just prior to histone replacement by protamines. Determination of chromatin's structural changes resulting from histone ubiquitination is therefore important. Recent work using reconstituted nucleosomes and chromatin fibers containing uH2A indicate that in the absence of linker histones, ubiquitination has little structural impact. DNase I digests and analytical ultracentrifugation of reconstituted ubiquitinated nucleosomes show no structural differences. Solubility assays using reconstituted chromatin fibers in the presence of divalent ions demonstrate that uH2A fibers are slightly more prone to aggregation than controls, and analytical ultracentrifugation results with different MgCl2 and NaCl concentrations determined that chromatin folding is not affected by this modification. Additional work to assess possible synergistic affects with histone acetylation also precludes any structural implications. Protamine displacement experiments concluded that the presence of uH2A does not significantly affect the ability of the protamines to displace histones. In addition, uH2A does not interfere with histone H1 binding to the nucleosome. While work with uH2B remains insufficient to come to any definitive conclusions about its structural impact, current work with uH-2A indicates that, contrary to predictions, this histone modification does not affect either nucleosome or chromatin structure. Consequently, the search for a structural role for ubiquitinated histones continues and their effect on and importance in chromatin dynamics remains elusive.

Animals↗

PubMed1990

Activation of M-phase-specific histone H1 kinase by modification of the phosphorylation of its p34cdc2 and cyclin components.

An M-phase-specific histone H1 kinase (H1K) has been described in a wide variety of eukaryotic cell types undergoing the G2/M transition in the cell division cycle. We have used p13suc1-Sepharose affinity chromatography to purify H1K to near homogeneity from matured starfish oocytes. A yield of 67% was obtained. Active H1K behaves as a 90- to 100-kD protein and appears to be constituted of equimolar amounts of cyclin and p34cdc2. The p34cdc2 subunit becomes tyrosine-dephosphorylated as the H1K is activated during entry of the oocytes into M phase, whereas the cyclin subunit is reciprocally phosphorylated. Acid phosphatase treatment of inactive p34cdc2/cyclin complex induces p34cdc2 dephosphorylation and three- to eightfold stimulation of the enzyme activity. These results suggest that active M-phase-specific H1K is constituted of both dephosphorylated p34cdc2 and phosphorylated cyclin.

Acid Phosphatase↗

PubMed1988

Structural changes of nucleosomal particles and isolated core-histone octamers induced by chemical modification of lysine residues.

Treatment of nucleosomal particles and isolated core-histone octamers with dimethylmaleic anhydride, but not with acetic anhydride, is accompanied by a biphasic release of the two H2A.H2B dimers, the first dimer being more easily released than the second. With both kinds of particles, 50% of histones H2A and H2B are released for modification of approximately 35% of the histone amino groups. The similar behavior of nucleosomal particles and isolated core-histone octamers is consistent with the same structure of the histone octamer in the nucleosomal particle and in the free octamer in 2 M NaCl. The described release of H2A.H2B dimers allows the preparation of nucleosomal particles deficient in one H2A.H2B dimer and of the histone hexamers H2A.H2B.(H3.H4)2. For more extensive modifications, both reagents, acetic and dimethylmaleic anhydrides, cause the dissociation of nucleosomal particles with liberation of double-stranded DNA, which suggests that lysine amino groups are involved in the binding of histones to DNA. The modified nucleosomal particles are more sensitive to ionic strength than those untreated, and the presence of salt (NaCl) increases the extent of DNA release. The histones corresponding to the liberated DNA, except H2A and H2B released with dimethylmaleic anhydride, are apparently bound to the DNA-containing particles as extra histones.

Acetic Anhydrides↗

PubMed2006

Epigenetics and airways disease.

Epigenetics is the term used to describe heritable changes in gene expression that are not coded in the DNA sequence itself but by post-translational modifications in DNA and histone proteins. These modifications include histone acetylation, methylation, ubiquitination, sumoylation and phosphorylation. Epigenetic regulation is not only critical for generating diversity of cell types during mammalian development, but it is also important for maintaining the stability and integrity of the expression profiles of different cell types. Until recently, the study of human disease has focused on genetic mechanisms rather than on non-coding events. However, it is becoming increasingly clear that disruption of epigenetic processes can lead to several major pathologies, including cancer, syndromes involving chromosomal instabilities, and mental retardation. Furthermore, the expression and activity of enzymes that regulate these epigenetic modifications have been reported to be abnormal in the airways of patients with respiratory disease. The development of new diagnostic tools might reveal other diseases that are caused by epigenetic alterations. These changes, despite being heritable and stably maintained, are also potentially reversible and there is scope for the development of 'epigenetic therapies' for disease.

Arginine↗

PubMedDate not supplied

Epigenetic silencing mediated by CpG island methylation: potential as a therapeutic target and as a biomarker.

Many genes become transcriptionally silenced during the development of cancer. As well as affecting disease progression, gene silencing has the potential to influence drug resistance and clinical outcome following therapy. In addition to silencing due to gene mutations, covalent epigenetic modifications such as DNA hypermethylation and histone post-translational modifications are associated with transcriptional inactivation of many genes and are an important early event during carcinogenesis and tumour development. Aberrant methylation of CpG islands in promoters is associated with transcriptional inactivation of genes involved in all aspects of tumour development. Genes involved in key DNA damage response pathways, such as cell cycle control, apoptosis signalling and DNA repair, can frequently become methylated and epigenetically silenced in tumours. This may lead to differences in intrinsic sensitivity of tumours to chemotherapy, depending on the specific function of the gene inactivated. Furthermore, it is proposed that chemotherapy itself can exert a selective pressure on epigenetically silenced drug sensitivity genes present in subpopulations of cells, leading to acquired chemoresistance. Since the DNA sequence of epigenetically inactivated genes are not mutated but rather subject to reversible modifications via DNA methyltransferases (DNMTs) or histone modification, it is possible to reverse silencing using small molecule inhibitors. Such compounds show anti-tumour activity and can increase the sensitivity of drug resistant preclinical tumour models. Clinical trials of epigenetic therapies are now underway. Epigenetic profiling, using DNA methylation and histone analysis, will provide guidance on optimisation of these therapies with conventional chemotherapy and will help identify patient populations who may particularly benefit from such approaches.

Animals↗

PubMed2003

Deubiquitination of histone H2B by a yeast acetyltransferase complex regulates transcription.

Post-translational modifications of the histone protein components of eukaryotic chromatin play an important role in the regulation of chromatin structure and gene expression (1). Given the requirement of Rad6/Bre1-dependent ubiquitination of histone H2B for H3 dimethylation (at lysines 4 and 79) and gene silencing (2-7), removal of ubiquitin from H2B may have a significant regulatory effect on transcription. Here we show that a putative deubiquitinating enzyme, Ubp8, is a structurally nonessential component of both the Spt-Ada-Gcn5-acetyltransferase (SAGA) and SAGA-like (SLIK) histone acetyltransferase (HAT) complexes in yeast. Disruption of this gene dramatically increases the cellular level of ubiquitinated-H2B, and SAGA and SLIK are shown to have H2B deubiquitinase activity. These findings demonstrate, for the first time, how the ubiquitin moiety can be removed from histone H2B in a regulated fashion. Ubp8 is required for full expression of the SAGA- and SLIK-dependent gene GAL10 and is recruited to the upstream activation sequence (UAS) of this gene under activating conditions, while Rad6 dissociates. Furthermore, trimethylation of H3 at lysine 4 within the UAS increases significantly under activating conditions, and remarkably, Ubp8 is shown to have a role in regulating the methylation status of this residue. Collectively, these data suggest that the SAGA and SLIK HAT complexes can regulate an integrated set of multiple histone modifications, counteracting repressive effects that alter chromatin and regulate gene expression.

Acetyltransferases↗

PubMed2006

Structural insights into histone demethylation by JMJD2 family members.

Posttranslational modifications of histones regulate chromatin structure and gene expression. Histone demethylases, members of a newly emerging transcription-factor family, remove methyl groups from the lysine residues of the histone tails and thereby regulate the transcriptional activity of target genes. JmjC-domain-containing proteins have been predicted to be demethylases. For example, the JmjC-containing protein JMJD2A has been characterized as a H3-K9me3- and H3-K36me3-specific demethylase. Here, structures of the catalytic-core domain of JMJD2A with and without alpha-ketoglutarate in the presence of Fe2+ have been determined by X-ray crystallography. The structure of the core domain, consisting of the JmjN domain, the JmjC domain, the C-terminal domain, and a zinc-finger motif, revealed the unique elements that form a potential substrate binding pocket. Sited-directed mutagenesis in conjunction with demethylase activity assays allowed us to propose a molecular model for substrate selection by the JMJD2 histone demethylase family.

Amino Acid Sequence↗

PubMed2005

Thanatos-associated protein 7 associates with template activating factor-Ibeta and inhibits histone acetylation to repress transcription.

The posttranslational modifications of histones on chromatin or a lack thereof is critical in transcriptional regulation. Emerging studies indicate a role for histone-binding proteins in transcriptional activation and repression. We have previously identified template-activating factor-Ibeta (TAF-Ibeta, also called PHAPII, SET, and I(2)(pp2A)) as a component of a cellular complex called inhibitor of acetyltransferases (INHAT) that masks histone acetylation in vitro and blocks histone acetyltransferase (HAT)-dependent transcription in living cells. TAF-Ibeta has also been shown to associate with transcription factors, including nuclear receptors, to regulate their activities. To identify novel interactors of TAF-Ibeta, we employed a yeast two-hybrid screen and identified a previously uncharacterized human protein called thanatos-associated protein-7 (THAP7), a member of a large family of THAP domain-containing putative DNA-binding proteins. In this study we demonstrate that THAP7 associates with TAF-Ibeta in vitro and map their association domains to a C-terminal predicted coiled-coil motif on THAP7 and the central region of TAF-Ibeta. Similarly, stably transfected THAP7 associates with endogenous TAF-Ibeta in intact cells. Like TAF-Ibeta, THAP7 associates with histone H3 and histone H4 and inhibits histone acetylation. The histone-interacting domain of THAP7 is sufficient for this activity in vitro. Promoter-targeted THAP7 can also recruit TAF-Ibeta and silencing mediator of retinoid and thyroid receptors/nuclear hormone receptor corepressor (NCoR) proteins to promoters, and knockdown of TAF-Ibeta by small interfering RNA relieves THAP7-mediated repression, indicating that, like nuclear hormone receptors, THAP7 may represent a novel class of transcription factor that uses TAF-Ibeta as a corepressor to maintain histones in a hypoacetylated, repressed state.

Acetylation↗

PubMed1997

Histone deacetylases and SAP18, a novel polypeptide, are components of a human Sin3 complex.

An important event in gene expression is the covalent modification of histone proteins. We have found that the mammalian transcriptional repressor Sin3 (mSin3) exists in a complex with histone deacetylases HDAC1 and HDAC2. Consistent with the observation that mSin3-mediated repression of transcription involves the modification of histone polypeptides, we found that the mSin3-containing complex includes polypeptides that tether the mSin3 complex to core histone proteins. In addition, two novel mSin3-associated polypeptides, SAP18 and SAP30, were identified. We isolated a cDNA encoding human SAP18 and found that SAP18 is a component of an mSin3-containing complex in vivo. Moreover, we demonstrate a direct interaction between SAP18 and mSin3. SAP18 represses transcription in vivo when tethered to the promoter, consistent with the ability of SAP18 to interact with mSin3.

Animals↗

PubMed2003

Cooperative interactions between epigenetic modifications and their function in the regulation of chromosome architecture.

Epigenetic information is encoded by DNA methylation and by covalent modifications of histone tails. While defined epigenetic modification patterns have been frequently correlated with particular states of gene activity, very little is known about the integration level of epigenetic signals. Recent experiments have resulted in the characterization of several epigenetic adaptors that mediate interactions between distinct modifications. These adaptors include methyl-DNA binding proteins, chromatin remodelling enzymes and siRNAs. Complex interactions between epigenetic modifiers and adaptors provide the foundation for the stability of epigenetic inheritance. In addition, they also provide an explanation for the long-range effects of epigenetic mechanisms. We propose that a major aspect of epigenetic regulation lies in the modification of chromosome architecture and that local changes in gene expression would be secondary consequences. This view is consistent with many results from recent genomic analyses.

Animals↗

PubMed2006

Chromatin structure and epigenetics.

In eukaryotic cells, the DNA molecule is found in the form of a nucleoprotein complex named chromatin. The basic unit of the chromatin is the nucleosome, which comprises 147 base pairs of DNA wrapped around an octamer of core histones (made of two molecules of each H2A, H2B, H3, and H4 histones). Each nucleosome is linked to the next by small segments of linker DNA. Most chromatin is further condensated by winding in a polynucleosome fibre, which may be stabilized through the binding of histone H1 to each nucleosome and to the linker DNA. The modulation of the structure of the chromatin fibre is critical for the regulation of gene expression since it determines the accessibility and the sequential recruitment of regulatory factors to the underlying DNA. Depending on the different transcriptional states, the structure of the chromatin may be altered in its constituents (e.g. the presence of repressors, activators, chromatin remodelling complexes, and/or incorporation of histone variants), and in covalent modifications of its constituents (such as DNA methylation at cytosine residues, and posttranslational modifications of histone tails). Here, we give an overview of the molecular mechanisms involved in chromatin regulation and the epigenetic transmission of its state, both in normal and pathological scenarios.

Animals↗

PubMed2003

Chromatin-dependent regulation of the MMTV promoter by cAMP signaling is mediated through distinct pathways.

The nucleoprotein structure of the mouse mammary tumor virus (MMTV) promoter defines its response to cAMP signaling. A stably replicating MMTV template in highly organized chromatin is repressed in the presence of cAMP, whereas a transiently transfected template with a disorganized structure is activated. In this study, we investigate the nature of the cAMP-induced signal(s) by which these opposing responses occur to gain insight into their mechanism. We demonstrate that the transcriptional changes observed at both templates are mediated through cAMP-dependent protein kinase A (PKA). In addition, the MMTV promoter lacks a consensus cAMP response element (CRE) and neither template requires cAMP response element-binding protein (CREB) to elicit a response to cAMP signaling. However, the responses of the two templates differ mechanistically in that the CREB-binding protein p300 potentiates activation from the transient template in a manner dependent on its Cys/His-rich region 3, but does not appear to affect the repression of the replicating chromatin template. Chromatin immunoprecipitation assays show that cAMP treatment results in a decrease in acetylation of histone H4, and in multiple modifications of histone H3 at specific nucleosomes in the promoter region of the stable MMTV template. These findings suggest novel CREB-independent, chromatin-dependent pathways for transcriptional regulation by cAMP.

8-Bromo Cyclic Adenosine Monophosphate↗