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PubMed2004

Selective recognition of acetylated histones by bromodomain proteins visualized in living cells.

Acetylation and other modifications on histones comprise histone codes that govern transcriptional regulatory processes in chromatin. Yet little is known how different histone codes are translated and put into action. Using fluorescence resonance energy transfer, we show that bromodomain-containing proteins recognize different patterns of acetylated histones in intact nuclei of living cells. The bromodomain protein Brd2 selectively interacted with acetylated lysine 12 on histone H4, whereas TAF(II)250 and PCAF recognized H3 and other acetylated histones, indicating fine specificity of histone recognition by different bromodomains. This hierarchy of interactions was also seen in direct peptide binding assays. Interaction with acetylated histone was essential for Brd2 to amplify transcription. Moreover association of Brd2, but not other bromodomain proteins, with acetylated chromatin persisted on chromosomes during mitosis. Thus the recognition of histone acetylation code by bromodomains is selective, is involved in transcription, and potentially conveys transcriptional memory across cell divisions.

Acetylation↗
PubMed1977

Localization of sequences coding for histone messenger RNA in the chromosomes of Drosophila melanogaster.

In situ hybridization of sea urchin (Psammechinus miliaris, Lytechinus pictus and Strongylocentrotus purpuratus) histone messenger RNA has been used to map complementary sequences on polytene chromosomes from Drosophila melanogaster. The sea urchin RNA hybridizes to the polytene regions from 39D3 through 39E1-2, including both of these bands (39D2 may also be included). This region is identical to the one which hybridizes most heavily with non-polyadenylated cytoplasmic RNA from D. melanogaster tissues. Sea urchin mRNAs coding for several individual histones each hybridize across the entire region from 39D3 (or D2) through 39E1-2, as would be expected if the individual mRNA sequences are interspersed. In view of the apparently even distribution of sequences complementary to histone mRNA within the 39D3-39E1-2 region, the significance of the several polytene bands in this region remains an open question. Biochemical characterization of the hybrids between sea urchin histone mRNA and D. melanogaster DNA suggest that sea urchin mRNAs for several of the histone classes have some portions which retain enough sequence homology with the D. melanogaster sequences to form hybrids, although the hybrids have base pair mismatches. In situ hybridization of chromosomes in which region 39-E is ectopically paired show no evidence of seqence homology in the chromosome region with which 39D-E is associated.

Animals↗
PubMed1995

The coding sequences of mouse H2A and H3 histone genes contains a conserved seven nucleotide element that interacts with nuclear factors and is necessary for normal expression.

Expression of replication-dependent histone genes of all classes is up-regulated coordinately at the onset of DNA synthesis. The cellular signals involved in coordinate regulation of these genes are not known. Here we report identification of an alpha element, present within the mouse histone coding region activating sequence (CRAS). We show evidence that this element is present in histone genes from two classes, H2a and H3, in the mouse. This element has two biological functions in histone gene expression, i.e. the element interacts with nuclear proteins in regulation of gene expression, as well as encoding the amino acids of the histone proteins. We present both in vivo and in vitro evidence that interaction of nuclear proteins with this element is required for normal expression. The binding site for nuclear protein(s) has been precisely defined by means of synthetic oligonucleotides, as well as DNase I protection and methylation interference. It is interesting to note that the histone CRAS alpha element is mutated in a replication-independent H3.3 gene; 5 of 7 nt in the CRAS alpha box are changed in this gene.

Animals↗
PubMedDate not supplied

Role of histone and transcription factor acetylation in diabetes pathogenesis.

Globally, diabetes (and, in particular, type 2 diabetes) represents a major challenge to world health. Currently in the United States, the costs of treating diabetes and its associated complications exceed 100 billion US dollars annually, and this figure is expected to soar in the near future. Despite decades of intense research efforts, the genetic basis of the events involved in the pathogenesis of diabetes is still poorly understood. Diabetes is a complex multigenic syndrome primarily due to beta-cell dysfunction associated with a variable degree of insulin resistance. Recent advances have led to exciting new developments with regard to our understanding of the mechanisms that regulate insulin transcription. These include data that implicate chromatin as a critical regulator of this event. The 'Histone Code' is a widely accepted hypothesis, whereby sequential modifications to the histones in chromatin lead to regulated transcription of genes. One of the modifications used in the histone code is acetylation. This is probably the best characterized modification of histones, which is carried out under the control of histone acetyltransferases (HATs) and histone deacetylases (HDACs). These enzymes also regulate the activity of a number of transcription factors through acetylation. Increasing evidence links possible dysregulation of these mechanisms in the pathogenesis of diabetes, with important therapeutic implications.

Acetylation↗
PubMed2003

Different sensitivities of bromodomain factors 1 and 2 to histone H4 acetylation.

The histone code hypothesis proposes that covalently modified histone tails are binding sites for specific proteins. In vitro evidence suggests that factors containing bromodomains read the code by binding acetylated histone tails. Bromodomain Factor 1 (Bdf1), a protein that associates with TFIID, binds histone H4 with preference for multiply acetylated forms. In contrast, the closely related protein Bdf2 shows no preference for acetylated forms. A deletion of BDF1 but not BDF2 is lethal when combined with a mutant allele of ESA1 (a histone H4 acetyltransferase) or with nonacetylatable histone H4 variants. Bromodomain point mutations that block Bdf1 binding to histones disrupt transcription and reduce Bdf1 association with chromatin in vivo. Therefore, bromodomains with different specificity generate further complexity of the histone code.

Acetylation↗
PubMed2006

Dynamic nucleosomes and gene transcription.

Gene transcription occurs on a nucleosomal template known as chromatin. The recruitment of the transcriptional regulators and the transcription machinery to promoter chromatin is coordinated by a genetic code on the DNA and an epigenetic code on the histone proteins. Chromatin is not a stable environment; rather, the histones, the transcription regulatory proteins and the enzymes that modify and mobilise nucleosomes are in a dynamic state. Thus, at any one time, the factors associated with a region will cooperate or compete to change the rate of inter-conversion between permissive and non-permissive chromatin states, leading to activation or repression of transcription. Here, new concepts such as dynamic nucleosomes and a dynamic histone code in gene transcription are explored.

Acetylation↗
PubMed2004

Nucleosome binding by the bromodomain and PHD finger of the transcriptional cofactor p300.

The PHD finger and the bromodomain are small protein domains that occur in many proteins associated with phenomena related to chromatin. The bromodomain has been shown to bind acetylated lysine residues on histone tails. Lysine acetylation is one of several histone modifications that have been proposed to form the basis for a mechanism for recording epigenetically stable marks in chromatin, known as the histone code. The bromodomain is therefore thought to read a part of the histone code. Since PHD fingers often occur in proteins next to bromodomains, we have tested the hypothesis that the PHD finger can also interact with nucleosomes. Using two different in vitro assays, we found that the bromodomain/PHD finger region of the transcriptional cofactor p300 can bind to nucleosomes that have a high degree of histone acetylation. In a nucleosome retention assay, both domains were required for binding. Replacement of the p300 PHD finger with other PHD fingers resulted in loss of nucleosome binding. In an electrophoretic mobility shift assay, each domain alone showed, however, nucleosome-binding activity. The binding of the isolated PHD finger to nucleosomes was independent of the histone acetylation levels. Our data are consistent with a model where the two domains cooperate in nucleosome binding. In this model, both the bromodomain and the PHD finger contact the nucleosome while simultaneously interacting with each other.

Histones↗
PubMed2006

[Histone variants and histone exchange].

Histones, as the basic components of nucleosome, are essential to chromatin structure and function. To adapt to various states of chromatin, corresponding histone variants are incorporated in nucleosome, and certain modifications also occur on the variants' tails. These variants change the conformation and stability of nucleosome to facilitate transcriptional activation or deactivation, DNA repairing, heterochromatin formation, and others. During histone exchange, chromatin remodeling complex facilitates histone variant deposition into nucleosome, and different variants have diverse deposition pathways. Recently, research on histone variants is not only a new hotspot in epigenetics, but also a new annotation of "histone code". In addition, histone exchange reveals new changing mechanism of DNA-histone interaction.

Animals↗
PubMed2003

[The epigenetic code of histones].

It has become clear that post-translational modifications of histones are key players in the mechanisms of transcriptional regulation. There are 4 major types of histone modifications: acetylation, methylation, phosphorylation and ubiquitinylation. Different combinations of these modifications would form an epigenetic code which, once read by specific protein domains, would lead to diverse responses at precise locations within the eukaryotic genome.

Epigenesis, Genetic↗
PubMed2006

Quantitative proteomic analysis of post-translational modifications of human histones.

Histone proteins are subject to a range of post-transcriptional modifications in living cells. The combinatorial nature of these modifications constitutes the "histone code" that dictates chromatin structure and function during development, growth, differentiation, and homeostasis of cells. Deciphering of the histone code is hampered by the lack of analytical methods for monitoring the combinatorial complexity of reversible multisite modifications of histones, including acetylation and methylation. To address this problem, we used LC-MSMS technology and Virtual Expert Mass Spectrometrist software for qualitative and quantitative proteomic analysis of histones extracted from human small cell lung cancer cells. A total of 32 acetylations, methylations, and ubiquitinations were located in the human histones H2A, H2B, H3, and H4, including seven novel modifications. An LC-MSMS-based method was applied in a quantitative proteomic study of the dose-response effect of the histone deacetylase inhibitor (HDACi) PXD101 on histone acetylation in human cell cultures. Triplicate LC-MSMS runs at six different HDACi concentrations demonstrated that PXD101 affects acetylation of histones H2A, H2B, H3, and H4 in a site-specific and dose-dependent manner. This unbiased analysis revealed that a relative increase in acetylated peptide from the histone variants H2A, H2B, and H4 was accompanied by a relative decrease of dimethylated Lys(57) from histone H2B. The dose-response results obtained by quantitative proteomics of histones from HDACi-treated cells were consistent with Western blot analysis of histone acetylation, cytotoxicity, and dose-dependent expression profiles of p21 and cyclin A2. This demonstrates that mass spectrometry-based quantitative proteomic analysis of post-translational modifications is a viable approach for functional analysis of candidate drugs, such as HDAC inhibitors.

Acetylation↗
PubMed2006

Chromosomal histone modification patterns--from conservation to diversity.

The organization of DNA into chromatin regulates expression and maintenance (replication, repair, recombination, segregation) of genetic information in a dynamic manner. The N-terminal tails of the nucleosomal core histones are subjected to post-translational modifications such as acetylation, methylation, phosphorylation, ubiquitination, glycosylation, ADP-ribosylation, carbonylation and sumoylation. These modifications, together with DNA methylation, control the folding of the nucleosomal array into higher order structures and mediate signalling for cellular processes. Although histones and their modifications are highly conserved, recent data show that chromosomal distribution of individual modifications (acetylation, methylation, phosphorylation) can differ along the cell cycle as well as among and between groups of eukaryotes. This implies the possibility of evolutionary divergence in reading the "histone code".

Acetylation↗
PubMed2003

Epigenetic theories of cancer initiation.

I argue that carcinogenic insults injure many cells rather than mutate a few. This results from evidence that such insults convert too many cells to a precancerous state and that too many of the converted cells then revert to plausibly involve mutation and its repair; from evidence that the delays between such insults and chemically demonstrable mutations are long enough to easily allow nonmutational mechanisms to work; from evidence that even ionizing radiation first acts on the cytoplasm and mainly affects cells unhit by it; from the fact that such insults induce proto-oncogene expression far too quickly to do so by mutation; and from the fact that fusions of various cells and cell parts show that the tumorous or nontumorous nature of the product depends on its cytoplasmic rather than its nuclear component. I further argue that reduced DNA methylation, modifications of the histone code, and tissue disorganization are the three main mechanisms of epigenetic cancer initiation. Hypomethylation would result from DNA excision repair. Moreover, a methyl-deficient diet is carcinogenic and demethylation is also known to be carcinogenic via the histone code. Finally, I strongly argue for tissue disorganization as a mechanism of cancer initiation. This results from evidence that skin carcinogens disrupt the dermal/epidermal connection and from the fact that tumorigens swiftly disrupt gap junctions, as well as from evidence that such disruption is tumorigenic.

Animals↗
PubMed1975

The organization of sea urchin histone genes.

Sucrose gradient analysis of total sea urchin DNA cleaved with the EcoRI and Hind III restriction endonucleases and identification of histone coding gene sequences by hybridization with histone mRNA have elucidated the basic organization of the histone gene repeat unit. These data, plus results obtained by electrophoretic analysis of purified endonuclease-cleaved sea urchin histone DNA and hybridization with cRNA transcribed from the eucaryotic segment of constructed plasmid chimeras cloned in E. coli, show that the several DNA sequences coding for individual histone proteins are intermingled in a 7 kilobase (kb) repeat unit. Cleavage of total sea urchin DNA with EcoRI produces 2.2 and 4.8 kb fragments, and which are contained in a 7 kb Hind III fragment. Cleavage with both enzymes reveals that the 2.2 kb EcoRI fragment contains a Hind III site 0.15--0.2 kb from an end. RNA.DNA hybridization between chimeric palsmic DNA and purified individual mRNAs isolated from sea urchin embryo polyribosomes has been used to assign coding sequences to either the 2.2 or 4.8 kb region of the histone DNA repeat unit. A map of the histone genes is proposed.

Animals↗
PubMed2005

Epigenetic regulation of mammalian pericentric heterochromatin in vivo by HP1.

We developed a model system whereby HP1 can be targeted to pericentric heterochromatin in ES cells lacking Suv(3)9h1/2 histone methyltransferase (HMTase) activities. HP1 so targeted can reconstitute tri-methylated lysine 9 of histone H3 (Me(3)K9H3) and tri-methylated lysine 20 of histone H4 (Me(3)K20H4) at pericentric heterochromatin, indicating that HP1 can regulate the distribution of these histone modifications in vivo. Both homo- and hetero-typic interactions between the HP1 isotypes were demonstrated in vivo as were HP1 interactions with the ESET/SETDB1 HMTase and the ATRX chromatin remodelling enzyme. We conclude that HP1 not only "deciphers" the histone code but can also "encode it".

Animals↗
PubMed2003

The double bromodomain protein Brd4 binds to acetylated chromatin during interphase and mitosis.

Previous in vitro studies showed that the bromodomain binds to acetyllysines on histone tails, leading to the proposal that the domain is involved in deciphering the histone code. However, there is little in vivo evidence supporting the binding of bromodomains to acetylated chromatin in the native environment. Brd4 is a member of the BET family that carries two bromodomains. It associates with mitotic chromosomes, a feature characteristic of the family. Here, we studied the interaction of Brd4 with chromatin in living cells by photobleaching. Brd4 was mobile and interacted with chromatin with a rapid "on and off" mode of binding. This interaction required both bromodomains. Indicating a preferential interaction with acetylated chromatin, Brd4 became less mobile upon increased chromatin acetylation caused by a histone deacetylase inhibitor. Providing biochemical support, salt solubility of Brd4 was markedly reduced upon increased histone acetylation. This change also required both bromodomains. In peptide binding assays, Brd4 avidly bound to di- and tetraacetylated histone H4 and diacetylated H3, but weakly or not at all to mono- and unacetylated H3 and H4. By contrast, it did not bind to unacetylated H4 or H3. Further, Brd4 colocalized with acetylated H4 and H3 in noncentromeric regions of mitotic chromosomes. This colocalization also required both bromodomains. These observations indicate that Brd4 specifically recognizes acetylated histone codes, and this recognition is passed onto the chromatin of newly divided cells.

Acetylation↗
PubMed1981

Orphons: dispersed genetic elements derived from tandem repetitive genes of eucaryotes.

We have discovered in animal cells a novel class of dispersed, solitary genetic elements derived from tandem multigene families. We refer to such displaced elements as orphons. Orphons arise from both protein-coding and non-protein-coding structural gene families, including those of histone and ribosomal genes. Southern transfer hybridization experiments, on DNA digested with enzymes that do not cut the major repeat unit of the family of genes of interest, reveal histone gene orphons in the sea urchin (Lytechinus pictus), ribosomal gene orphons in yeast (Saccharomyces cerevisiae) and ribosomal and H3 histone gene orphons in Drosophila melanogaster. There are more than 50 histone gene orphons in each sea urchin genome. Each of the five histone-coding regions has a number of orphons (5--20), in addition to the several hundred copies in the clusters that are not cut by Bam HI. Most such orphons appear to contain only one coding region. Nearly all sea urchin histone gene orphon loci are polymorphic in the population; no two individuals have the same sets of histone orphons for any coding region. An H3-coding orphon, pLpH30-1, was isolated from the genome of L. pictus. The H3 region homologous to the histone gene clusters is 1200 bases long and includes the complete early H3 gene and some surrounding histone DNA. THe orphon is flanked by at least 1.7 kb of 5' and 3 kb of 3' nonhistone DNA. These flanking sequences are each moderately repetitive in the genome and are not homologous to each other. The orphon differs less than 2% in base sequence from the analogous region of pLpC and only slightly more from pLpA (the major histone gene clones). DNA sequence analysis of the junctions between the H3 region and the immediate flanking nonhistone DNA reveals no evidence of repetitive or palindromic sequences.

Animals↗
PubMed2005

Modifications of human histone H3 variants during mitosis.

Phosphorylation of histone H3 is a hallmark event in mitosis and is associated with chromosome condensation. Here, we use a combination of immobilized metal affinity chromatography and tandem mass spectrometry to characterize post-translational modifications associated with phosphorylation on the N-terminal tails of histone H3 variants purified from mitotically arrested HeLa cells. Modifications observed in vivo on lysine residues adjacent to phosphorylated Ser and Thr provide support for the existence of the "methyl/phos", binary-switch hypothesis [Fischle, W., Wang, Y., and Allis, C. D. (2003) Nature 425, 475-479]. ELISA with antibodies selective for H3 at Ser10, Ser28, and Thr3 show reduced activity when adjacent Lys residues are modified. When used together, mass spectrometry and immunoassay methods provide a powerful approach for elucidation of the histone code and identification of histone post-translational modifications that occur during mitosis and other specific cellular events.

Chromatography, Affinity↗