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Post-translational modifications of histones H3 and H4 associated with the histone methyltransferases Suv39h1 and G9a
Philippe Robin, Lauriane Fritsch, Ophélie Philipot, Fedor Svinarchuk, Slimane Ait-Si-Ali
Genome Biology , 2007, DOI: 10.1186/gb-2007-8-12-r270
Abstract: The amino-terminal tails of nucleosomal histones protrude from the DNA and are subject to covalent modifications. These modifications include lysine acetylation, lysine and arginine methylation, serine and threonine phosphorylation, ADP-ribosylation, and ubiquitination [1]. Histone lysine methylation can have different effects depending on the residue that is modified: methylation of histone H3 at Lys4 (H3K4) is associated with gene activation, whereas methylation of H3K9, H3K27, and H4K20 generally correlates with transcriptional repression [2-4]. The roles of H3K36 and H3K79 methylation remain elusive; indeed, these modifications are associated with both transcriptional activation and repression [5,6].Lysine residues can be mono-, di-, or trimethylated, inducing different biological responses [3,7,8]. Thus, for example, highly condensed heterochromatic regions show a high degree of trimethylated H3K9 (H3K9me3), whereas euchromatic regions are preferentially enriched in mono- and dimethylated H3K9 [2,3]. Histone lysine methylation is mediated by histone methyltransferases (HMTs), many of which contain a conserved SET [Su(var)3-9, Enhancer-of-zeste, Trithorax] domain, such as Suv39h1 (Suppressor of variegation 39h1) and G9a [1,2,9]. Suv39h1 belongs to a family of peri-centromeric proteins and is responsible for H3K9 trimethylation [10-13]. G9a (EuHMTase-2) is the major methylase responsible for mono- and dimethylation of H3K9 in euchromatic regions [14,15], but it may also be present in heterochomatic regions [16].Covalent modifications of histones can regulate gene expression directly or through recruitment of non-histone effector proteins [2,17]. These effector proteins bind modified chromatin using a variety of chromatin-binding domains. For example, bromodomains recognize acetylated lysines, whereas chromo, MBT, Tudor, W40 domains and PHD fingers, recognize methylated lysines [17,18]. Repressive methyl-lysine modifications are recognized by chromodomain-containi
Enhanced top-down characterization of histone post-translational modifications
Zhixin Tian, Nikola Toli?, Rui Zhao, Ronald J Moore, Shawna M Hengel, Errol W Robinson, David L Stenoien, Si Wu, Richard D Smith, Ljiljana Pa?a-Toli?
Genome Biology , 2012, DOI: 10.1186/gb-2012-13-10-r86
Abstract: Histones are important chromatin proteins that act as spools to package and order DNA into structural and manageable chromosomes. Core histones are modified by multiple post-translational modifications (PTMs) such as lysine acetylation, lysine or arginine methylation, and serine or threonine phosphorylation, among others. These PTMs generate a 'histone code' [1] that is implicated in chromatin-related cellular processes [2] including transcription [3], replication [4], repair [5], and alternative splicing [6].Although core histones comprise only four families (H4, H2B, H2A, and H3), each family has thousands of potential isoforms generated by different combinations of PTMs and protein sequence variation. Traditional antibody-based methods target specific isoforms, typically analyzing one PTM at a time, which makes it virtually impossible to measure combinatorial modifications occurring within the same histone molecule. Recently, high-throughput bottom-up [7] and middle-down [8] proteomic methods demonstrated potential for global characterization of PTMs on histone tails. However, these methods are ill-suited for characterizing multiple PTMs dispersed along the entire protein sequence that have been previously discovered to have significant participation in chromatin regulation [2,9-11].Top-down proteomic and high-throughput approaches are clearly required to identify and quantify the modulation of multiple intra-molecular histone modifications that synergistically regulate histone functions. Recently, a global top-down study demonstrated the feasibility of intact protein analysis for this purpose by identifying more than 300 histone isoforms using extensive fractionation and customized bioinformatics for global proteome characterization [12]. In histone-focused studies, top-down approaches using an offline two-dimensional liquid chromatography (2D LC) separation and Fourier transform mass spectrometry (FTMS) characterized 34 H4 isoforms from approximately 150 μg of
Global turnover of histone post-translational modifications and variants in human cells
Barry M Zee, Rebecca S Levin, Peter A DiMaggio, Benjamin A Garcia
Epigenetics & Chromatin , 2010, DOI: 10.1186/1756-8935-3-22
Abstract: In this study, we measured the metabolic rate of labeled isotope incorporation into the histone proteins of HeLa cells by combining stable isotope labeling of amino acids in cell culture (SILAC) pulse experiments with quantitative mass spectrometry-based proteomics. In general, we found that most core histones have similar turnover rates, with the exception of the H2A variants, which exhibit a wider range of rates, potentially consistent with their epigenetic function. In addition, acetylated histones have a significantly faster turnover compared with general histone protein and methylated histones, although these rates vary considerably, depending on the site and overall degree of methylation. Histones containing transcriptionally active marks have been consistently found to have faster turnover rates than histones containing silent marks. Interestingly, the presence of both active and silent marks on the same peptide resulted in a slower turnover rate than either mark alone on that same peptide. Lastly, we observed little difference in the turnover between nearly all modified forms of the H3.1, H3.2 and H3.3 variants, with the notable exception that H3.2K36me2 has a faster turnover than this mark on the other H3 variants.Quantitative proteomics provides complementary insight to previous work aimed at quantitatively measuring histone turnover, and our results suggest that turnover rates are dependent upon site-specific post-translational modifications and sequence variants.In eukaryotes, stable genetic storage is accomplished through the local organization of DNA around histone proteins to form the chromatin fiber. Histones have been long recognized as the structural scaffolds of chromatin, but more recent research has suggested that they possess a broader role. The epigenetic influence of histones is mediated primarily by post-translational modifications (PTMs) and also by selective deposition of histone variants, which in combination influence gene transcription
Histone Acetyl Transferase 1 Is Essential for Mammalian Development, Genome Stability, and the Processing of Newly Synthesized Histones H3 and H4  [PDF]
Prabakaran Nagarajan,Zhongqi Ge,Bianca Sirbu,Cheryl Doughty,Paula A. Agudelo Garcia,Michaela Schlederer,Anthony T. Annunziato,David Cortez,Lukas Kenner,Mark R. Parthun
PLOS Genetics , 2013, DOI: 10.1371/journal.pgen.1003518
Abstract: Histone acetyltransferase 1 is an evolutionarily conserved type B histone acetyltransferase that is thought to be responsible for the diacetylation of newly synthesized histone H4 on lysines 5 and 12 during chromatin assembly. To understand the function of this enzyme in a complex organism, we have constructed a conditional mouse knockout model of Hat1. Murine Hat1 is essential for viability, as homozygous deletion of Hat1 results in neonatal lethality. The lungs of embryos and pups genetically deficient in Hat1 were much less mature upon histological evaluation. The neonatal lethality is due to severe defects in lung development that result in less aeration and respiratory distress. Many of the Hat1?/? neonates also display significant craniofacial defects with abnormalities in the bones of the skull and jaw. Hat1?/? mouse embryonic fibroblasts (MEFs) are defective in cell proliferation and are sensitive to DNA damaging agents. In addition, the Hat1?/? MEFs display a marked increase in genome instability. Analysis of histone dynamics at sites of replication-coupled chromatin assembly demonstrates that Hat1 is not only responsible for the acetylation of newly synthesized histone H4 but is also required to maintain the acetylation of histone H3 on lysines 9, 18, and 27 during replication-coupled chromatin assembly.
Plasticity of Fission Yeast CENP-A Chromatin Driven by Relative Levels of Histone H3 and H4  [PDF]
Araceli G Castillo equal contributor,Barbara G Mellone equal contributor,Janet F Partridge,William Richardson,Georgina L Hamilton,Robin C Allshire ,Alison L Pidoux
PLOS Genetics , 2007, DOI: 10.1371/journal.pgen.0030121
Abstract: The histone H3 variant CENP-A assembles into chromatin exclusively at centromeres. The process of CENP-A chromatin assembly is epigenetically regulated. Fission yeast centromeres are composed of a central kinetochore domain on which CENP-A chromatin is assembled, and this is flanked by heterochromatin. Marker genes are silenced when placed within kinetochore or heterochromatin domains. It is not known if fission yeast CENP-ACnp1 chromatin is confined to specific sequences or whether histone H3 is actively excluded. Here, we show that fission yeast CENP-ACnp1 can assemble on noncentromeric DNA when it is inserted within the central kinetochore domain, suggesting that in fission yeast CENP-ACnp1 chromatin assembly is driven by the context of a sequence rather than the underlying DNA sequence itself. Silencing in the central domain is correlated with the amount of CENP-ACnp1 associated with the marker gene and is also affected by the relative level of histone H3. Our analyses indicate that kinetochore integrity is dependent on maintaining the normal ratio of H3 and H4. Excess H3 competes with CENP-ACnp1 for assembly into central domain chromatin, resulting in less CENP-ACnp1 and other kinetochore proteins at centromeres causing defective kinetochore function, which is manifest as aberrant mitotic chromosome segregation. Alterations in the levels of H3 relative to H4 and CENP-ACnp1 influence the extent of DNA at centromeres that is packaged in CENP-ACnp1 chromatin and the composition of this chromatin. Thus, CENP-ACnp1 chromatin assembly in fission yeast exhibits plasticity with respect to the underlying sequences and is sensitive to the levels of CENP-ACnp1 and other core histones.
Histone modifications: from genome-wide maps to functional insights
Fred van Leeuwen, Bas van Steensel
Genome Biology , 2005, DOI: 10.1186/gb-2005-6-6-113
Abstract: The DNA in the nucleus of a eukaryotic cell is packed into chromatin, the fundamental building block of which, the nucleosome, consists of an octamer of the four histones H2A, H2B, H3 and H4, around which the DNA is wrapped. The histones within chromatin are subject to extensive post-translational modification, including acetylation, methylation, phosphorylation, ubiquitination, and ribosylation. Many enzymes have been identified that are responsible for the addition or removal of modifications at one or a few specific histone amino-acid residues, and many histone modifications are believed to play important roles in the regulation of transcription. Although some histone modifications may cause alterations in the structure or overall charge of the nucleosome [1,2], it is likely that most act by controlling the docking of specific regulatory factors. For example, the chromodomain of heterochromatin protein 1 (HP1) binds to the tail of histone H3 only when lysine 9 of H3 (H3K9) is methylated, and this may contribute to repression of transcription [3]. Similarly, the bromodomains of various transcriptional activators and nucleosome-remodeling factors recognize specific acetylated lysine residues within histone H3 or H4 [4]. While some modifications attract specific regulatory factors, others appear to block protein binding. This is illustrated by the inhibitory effect of acetylation on the binding of the silencing protein Sir3 to histone H4 [5]. Undoubtedly, many more factors will be discovered that recognize particular modification states of histones.Given the large number of histone modifications that appear to be involved in the control of gene expression, the integration of their regulatory roles is an important issue. How do these modifications work together? For example, H3K4 methylation and H3K9 acetylation have both been implicated in gene activation; do these two modifications typically act together on a common set of genes, or are they part of separate signal
Induction of Apoptosis and Acetylation of Histone H3 and H4 by Arctigenin in the Human Melanoma Cell Line SK-MEL-28  [PDF]
Jin Boo Jeong, Se Chul Hong, Jin Suk Koo, Hyung Jin Jeong
Food and Nutrition Sciences (FNS) , 2011, DOI: 10.4236/fns.2011.22018
Abstract: Cutaneous melanoma is one of the most aggressive forms of skin cancer. Arctigenin, one of the major bioactive compo-nents of Arctii Fructus, has been reported to exhibit antioxidant, antitumor and anti-inflammatory activities. In the pre-sent study, we investigated the effect of arctigenin on induction of apoptosis in highly metastatic SK-MEL-28 human melanoma cells. Arctigenin inhibited growth of SK-MEL-28 cells in a dose-dependent manner. Treatment of SK-MEL-28cells with arctigenin caused cleavage of caspases 3, 7 and 9, and poly (ADP-ribose) polymerase in a dose-dependent manner. Furthermore, acetylation of histone H3 and H4 in the SK-MEL-28 cells was dramatically increased by arctigenin treatment. Collectively, these findings indicate that arctigenin-induces apoptosis of SK-MEL-28 melanoma cells via activation of caspases and histone acetylation.
Histone Variants and Their Post-Translational Modifications in Primary Human Fat Cells  [PDF]
?sa Jufvas,Peter Str?lfors,Alexander V. Vener
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0015960
Abstract: Epigenetic changes related to human disease cannot be fully addressed by studies of cells from cultures or from other mammals. We isolated human fat cells from subcutaneous abdominal fat tissue of female subjects and extracted histones from either purified nuclei or intact cells. Direct acid extraction of whole adipocytes was more efficient, yielding about 100 μg of protein with histone content of 60% –70% from 10 mL of fat cells. Differential proteolysis of the protein extracts by trypsin or ArgC-protease followed by nanoLC/MS/MS with alternating CID/ETD peptide sequencing identified 19 histone variants. Four variants were found at the protein level for the first time; particularly HIST2H4B was identified besides the only H4 isoform earlier known to be expressed in humans. Three of the found H2A potentially organize small nucleosomes in transcriptionally active chromatin, while two H2AFY variants inactivate X chromosome in female cells. HIST1H2BA and three of the identified H1 variants had earlier been described only as oocyte or testis specific histones. H2AFX and H2AFY revealed differential and variable N-terminal processing. Out of 78 histone modifications by acetylation/trimethylation, methylation, dimethylation, phosphorylation and ubiquitination, identified from six subjects, 68 were found for the first time. Only 23 of these modifications were detected in two or more subjects, while all the others were individual specific. The direct acid extraction of adipocytes allows for personal epigenetic analyses of human fat tissue, for profiling of histone modifications related to obesity, diabetes and metabolic syndrome, as well as for selection of individual medical treatments.
Tousled kinase TLK1B counteracts the effect of Asf1 in inhibition of histone H3–H4 tetramer formation
Arrigo De Benedetti
BMC Research Notes , 2009, DOI: 10.1186/1756-0500-2-128
Abstract: We have used protein crosslinking with purified components to probe the interaction between H3, H4, Asf1, and TLK1B. We found that TLK1B, by virtue of its binding to Asf1, can restore formation of H3–H4 tetramers that is sterically prevented by adding Asf1.We suggest that TLK1B binds to Asf1 in a manner that interferes with its binding to the H3–H4 dimer, thereby allowing for H3–H4 tetramerization. A description of the function of TLK1 and Asf1 in chromatin remodeling is presented.The gene Tousled of Arabidopsis thaliana encodes a protein kinase which, when mutated, results in abnormal flower development [1], possibly from failure to protect the genome from UV damage [2,3] and resulting in mitotic aberrations [4,5]. Alternatively, the defects may involve other activities of Tousled like kinases (TLKs) in transcription [6], or in segregation of chromosomes at mitosis [4,7]. Several physiological substrates of Tousled kinases have been identified, namely Asf1 [8], histone H3 [9], and more recently Rad9 [10], which suggested a function in chromatin assembly [11] with implications in transcription [12,2], condensation of chromosomes [4], and DNA repair [3,13]. TLK1 is generally considered a gene of metazoans, although TLK1 is also present in trypanosomes [14]. In all mammals studied, the primary TLK1 transcript is alternatively spliced to two main isoforms [15,9] termed TLK1 and TLK1B, which probably have very similar function [10], and that we often refer to as TLK1/1B. TLK1/1B binds and phosphorylates Asf1 in all organisms in which it is found, with the exception of yeast [8], despite the conservation of Asf1 among all species.Asf1 is a histone H3–H4 chaperone [16] that is essential in mammalian cells [17] and other organisms [18] but not in yeast, although yeast cells deleted for Asf1 are sensitive to genotoxins [19]. Asf1, in conjunction with CAF1, promotes the assembly of nucleosomes onto newly replicated DNA, but it can also promote nucleosome eviction at activate
Molecular Recognition of H3/H4 Histone Tails by the Tudor Domains of JMJD2A: A Comparative Molecular Dynamics Simulations Study  [PDF]
Musa Ozboyaci,Attila Gursoy,Burak Erman,Ozlem Keskin
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0014765
Abstract: Histone demethylase, JMJD2A, specifically recognizes and binds to methylated lysine residues at histone H3 and H4 tails (especially trimethylated H3K4 (H3K4me3), trimethylated H3K9 (H3K9me3) and di,trimethylated H4K20 (H4K20me2, H4K20me3)) via its tandem tudor domains. Crystal structures of JMJD2A-tudor binding to H3K4me3 and H4K20me3 peptides are available whereas the others are not. Complete picture of the recognition of the four histone peptides by the tandem tudor domains yet remains to be clarified.
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