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PubMed2001

Physical association between the histone acetyl transferase CBP and a histone methyl transferase.

CBP (CREB-binding protein) is involved in transcriptional activation by a great variety of sequence-specific transcription factors. CBP has been shown to activate transcription through its histone acetyl transferase activity. Acetylation is a common post-translational modification of nucleosomal histone N-terminal tails, which generally correlates with transcriptional activation. Histone N-terminal tails are also modified by methylation but its functional consequences are largely unknown. Here we found that immunoprecipitation of CBP, or of the highly related p300, led to the co-immunoprecipitation of a robust histone methyl transferase (HMT) activity, indicating that CBP physically interacts with an HMT in living cells. The CBP-associated HMT is specific for lysines 4 and 9 of histone H3, which are known to be methylated in living cells. These results suggest that histone methylation could be involved in transcriptional activation. Furthermore, they raise the question of the link between histone methylation and acetylation.

Acetylation↗
PubMed1998

Nucleosome and chromatin structures and functions.

From the above discussion it can be appreciated that the major unknowns to advancing our understanding of nucleosome and chromatin structure and functions are: 1) the binding sites of the histone N- and C-terminal domains in native nucleosomes and in chromatin; 2) the effects of histone reversible chemical modifications of phosphorylations, acetylations and ubiquitinations on the binding of the histone N- and C-terminal domains in nucleosome and chromatin structures; 3) the path(s) of the linker DNA between nucleosome in the different orders of chromatin structure; 4) the position of the globular, N- and C-terminal domains of linker histones in the nucleosome and chromatin structures; and 5) the lack of a detailed structure for the 30 nm chromatin fiber. The above unknowns provide formidable challenges for future researchers.

Animals↗
PubMed1976

Histone content in relation to amount of heterochromatin and developmental stage in three species of Drosophila.

Relative amounts of various histone fractions in Drosophila chromatin were estimated densitometrically on electrophoretic gel separations. Several consistent and highly significant differences were obtained between larval and adult chromatin. The arginine-rich histones showed the most conspicuous changes: higher amounts of H4 in larvae, higher H3 in adults. The level of modification of these histones was clearly higher in larval than in adult chromatin. The modification of the two slower subfractions of H4 involved, in all probability, phosphorylation as well as acetylation. In all types of Drosophila chromatin studied 50% or more of the H2a molecules were phosphorylated--a remarkably high proportion. The species differences observed in relative amounts of histone were consistent in both stages of development. D. melanogaster differed from D. hydei and D. virilis in all histones except H2b, while the latter two species were generally similar. The interspecific variation in histone pattern was generally not correlated to differences in content of heterochromatin. The level of modification of H2 was, however, presumably an exception, as it was significantly lower for both larvae and adults in D. virilis than in the other two species. These differ from D. virilis in containing appreciably lower proportions of heterochromatic chromosome segments.

Animals↗
PubMed2004

Chromatin immunoprecipitation microarrays for identification of genes silenced by histone H3 lysine 9 methylation.

Switching from acetylation to methylation at histone H3 lysine 9 (K9) has recently been shown to contribute to euchromatin gene silencing. To identify genes silenced by K9 modifications, we probed a human CpG island microarray with DNA obtained by chromatin immunoprecipitation (ChIP) in a cancer cell line using an anti-H3-K9 methylated antibody or an anti-H3-K9 acetylated antibody. Of the 27 clones with the highest signal ratio of K9 methylation over acetylation (Me/Ac), 13 contained repetitive sequences. Among 14 nonrepetitive clones, we identified 11 genes (seven known and four previously undescribed), one EST, and two unknown fragments. Using ChIP-PCR, all 18 examined clones showed higher ratios of H3-K9 Me/Ac than the active gene control, P21, thus confirming the microarray data. In addition, we found a strong correlation between the K9 Me/Ac ratio and CpG island DNA methylation (R = 0.92, P < 0.01), and five of seven genes examined (megalin, thrombospondin-4, KR18, latrophilin-3, and phosphatidylinositol-3-OH kinase P101 subunit) showed lack of expression by RT-PCR and reactivation by DNA methylation and/or histone deacetylase inhibition, suggesting that these genes are true targets of silencing through histone modifications. All five genes also showed significant DNA methylation in a cell line panel and in primary colon cancers. Our data suggest that CpG island microarray coupled with ChIP can identify novel targets of gene silencing in cancer. This unbiased approach confirms the tight coupling between DNA methylation and histone modifications in cancer and could be used to probe gene silencing in nonneoplastic conditions as well.

Acetylation↗
PubMed2005

siRNA-mediated transcriptional gene silencing: the potential mechanism and a possible role in the histone code.

Epigenetics is the study of meiotically and mitotically heritable changes in gene expression which are not coded for in the DNA. Three distinct mechanisms appear intricately related in initiating and sustaining epigenetic modifications: RNA-associated silencing, DNA methylation and histone modification. Recently, in human cells small-interfering RNAs (siRNAs) have been shown to mediate transcriptional gene silencing (TGS). The observation that siRNAs can function to suppress gene expression at the level of transcription has created a major paradigm shift in mammalian RNA interference. The putative mechanism(s) of siRNA-mediated TGS in both yeast and human cells will be discussed. Undoubtedly, the ramifications from this paradigm shift in which RNA has demonstrated a potent and specific capability to regulate the expression of the gene are immeasurable both therapeutically (i. e. directed control of gene expression) and biologically in understanding the evolution of the cell.

Animals↗
PubMed2002

Methylation of histone H3 by COMPASS requires ubiquitination of histone H2B by Rad6.

The DNA of eukaryotes is wrapped around nucleosomes and packaged into chromatin. Covalent modifications of the histone proteins that comprise the nucleosome alter chromatin structure and have major effects on gene expression. Methylation of lysine 4 of histone H3 by COMPASS is required for silencing of genes located near chromosome telomeres and within the rDNA (Krogan, N. J, Dover, J., Khorrami, S., Greenblatt, J. F., Schneider, J., Johnston, M., and Shilatifard, A. (2002) J. Biol. Chem. 277, 10753-10755; Briggs, S. D., Bryk, M., Strahl, B. D., Cheung, W. L., Davie, J. K., Dent, S. Y., Winston, F., and Allis, C. D. (2001) Genes. Dev. 15, 3286-3295). To learn about the mechanism of histone methylation, we surveyed the genome of the yeast Saccharomyces cerevisiae for genes necessary for this process. By analyzing approximately 4800 mutant strains, each deleted for a different non-essential gene, we discovered that the ubiquitin-conjugating enzyme Rad6 is required for methylation of lysine 4 of histone H3. Ubiquitination of histone H2B on lysine 123 is the signal for the methylation of histone H3, which leads to silencing of genes located near telomeres.

DNA, Ribosomal↗
PubMed2005

Methylation patterns of histone H3 Lys 4, Lys 9 and Lys 27 in transcriptionally active and inactive Arabidopsis genes and in atx1 mutants.

Covalent modifications of histone-tail amino acid residues communicate information via a specific 'histone code'. Here, we report histone H3-tail lysine methylation profiles of several Arabidopsis genes in correlation with their transcriptional activity and the input of the epigenetic factor ARABIDOPSIS HOMOLOG OF TRITHORAX (ATX1) at ATX1-regulated loci. By chromatin immunoprecipitation (ChIP) assays, we compared modification patterns of a constitutively expressed housekeeping gene, of a tissue-specific gene, and among genes that differed in degrees of transcriptional activity. Our results suggest that the di-methylated isoform of histone H3-lysine4 (m2K4/H3) provide a general mark for gene-related sequences distinguishing them from non-transcribed regions. Lys-4 (K4/H3), lys-9 (K9/H3) and lys-27 (K27/H3) nucleosome methylation patterns of plant genes may be gene-, tissue- or development-regulated. Absence of nucleosomes from the LTP-promotor was not sufficient to provoke robust transcription in mutant atx1-leaf chromatin, suggesting that the mechanism repositioning nucleosomes at transition to flowering functioned independently of ATX1.

Arabidopsis↗
PubMed2006

A trans-tail histone code defined by monomethylated H4 Lys-20 and H3 Lys-9 demarcates distinct regions of silent chromatin.

The specific post-translational modifications of the histone proteins are associated with specific DNA-templated processes, such as transcriptional activation or repression. To investigate the biological role(s) of histone H4 lysine 20 (H4 Lys-20) methylation, we created a novel panel of antibodies that specifically detected mono-, di-, or trimethylated H4 Lys-20. We report that the different methylated forms of H4 Lys-20 are compartmentalized within visually distinct, transcriptionally silent regions in the mammalian nucleus. Interestingly, direct comparison of methylated H4 Lys-20 with the different methylated states of histone H3 lysine 9 (H3 Lys-9) revealed significant overlap and exclusion between the specific groups of methyl modifications. Trimethylated H4 Lys-20 and H3 Lys-9 were both selectively enriched within pericentric heterochromatin. Similarly, monomethylated H4 Lys-20 and H3 Lys-9 partitioned together and the dimethylated forms partitioned together within the chromosome arms; however, the mono- and dimethylated modifications were virtually exclusive. These findings strongly suggest that the combinatorial presence or absence of the different methylated states of H4 Lys-20 and H3 Lys-9 define particular types of silent chromatin. Consistent with this, detailed analysis of monomethylated H4 Lys-20 and H3 Lys-9 revealed that both were preferentially and selectively enriched within the same nucleosome particle in vivo. Collectively, these findings define a novel trans-tail histone code involving monomethylated H4 Lys-20 and H3 Lys-9 that act cooperatively to mark distinct regions of silent chromatin within the mammalian epigenome.

Amino Acid Sequence↗
PubMed1984

Relaxation of chromatin structure upon removal of histones H2A and H2B.

Modification of chromatin from chicken erythrocytes with dimethylmaleic anhydride is accompanied by its solubilization and the dissociation of histones H1, H5, H2A and H2B. Histone H1 is the first to dissociate and H5 the last. After regeneration of the modified amino groups, residual chromatin preparations with different histone composition were studied by circular dichroism and thermal denaturation. In addition to the effects produced by the lack of histones H1 and H5, both techniques show a substantial relaxation of chromatin structure induced by the loss of histones H2A and H2B, which appear to play an important role in the superhelical folding of DNA.

Animals↗
PubMed2006

Immunohistochemical analysis of histone H3 acetylation and methylation--evidence for altered epigenetic signaling following traumatic brain injury in immature rats.

Posttranslational modifications (PTMs) of histone proteins may result in altered epigenetic signaling after pediatric traumatic brain injury (TBI). Hippocampal histone H3 acetylation and methylation in immature rats after moderate TBI were measured and decreased only in CA3 at 6 h and 24 h with persistent methylation decreases up to 72 h after injury. Decreased histone H3 acetylation and methylation suggest altered hippocampal CA3 epigenetic signaling during the first hours to days after TBI.

Acetylation↗
PubMed2005

Transcription factor interactions and chromatin modifications associated with p53-mediated, developmental repression of the alpha-fetoprotein gene.

We performed chromatin immunoprecipitation (ChIP) analyses of developmentally staged solid tissues isolated from wild-type and p53-null mice to determine specific histone N-terminal modifications, histone-modifying proteins, and transcription factor interactions at the developmental repressor region (-850) and core promoter of the hepatic tumor marker alpha-fetoprotein (AFP) gene. Both repression of AFP during liver development and silencing in the brain, where AFP is never expressed, are associated with dimethylation of histone H3 lysine 9 (DiMetH3K9) and the presence of heterochromatin protein 1 (HP1). These heterochromatic markers remain localized to AFP during developmental repression but spread to the upstream albumin gene during silencing. Developmentally regulated decreases in levels of acetylated H3 (AcH3K9) and H4 (AcH4) and of di- and trimethylated H3K4 (DiMetH3K4 and TriMetH3K4) occur at both the core promoter and distal repressor regions of AFP. Hepatic expression of AFP correlates with FoxA interaction at the repressor region and the binding of RNA polymerase II and TATA-binding protein to the core promoter. p53 acts as a developmental repressor of AFP in the liver by binding to chromatin, excluding FoxA interaction and targeting mSin3A/HDAC1 to the distal repressor region. p53-null mice exhibit developmentally delayed AFP repression, concomitant with acetylation of H3K9, methylation of H3K4, and loss of DiMetH3K9, mSin3A/HDAC1, and HP1 interactions.

Acetylation↗
PubMed2006

The malaria parasite Plasmodium falciparum histones: organization, expression, and acetylation.

Histones are the building units of nucleosomes and play essential roles in DNA replication, repair and transcription. A comprehensive analysis of histone genes revealed that the Plasmodium falciparum genome encodes a canonical form of each core histone and four histone variants H2A.Z, H3.3, centromere-specific H3 (CenH3), and H2Bv. Mass spectrometry confirmed the synthesis of all histones except CenH3. Real-time reverse transcriptase-polymerase chain reaction and immunoblotting detected a dramatic increase in core histone gene expression during the late trophozoite stages, consistent with their role in replication-related nucleosome assembly. In contrast, the expression of variant histones decreased in mid- or late trophozoite stages. The N-terminal tails of histones participate in transcription regulation through covalent modifications, especially at the lysine residues. In accordance, mass spectrometry analysis revealed acetylation of lysines and methylation of lysines and arginines in the N-termini of H3, H3.3, and H4. Moreover, we identified a new pattern of lysine modifications of the H2A.Z variant. Using a panel of acetylation-specific antibodies, we found that K5, K8, and K12 of H4 were abundantly acetylated at a relatively steady level throughout the erythrocytic cycle. In comparison, the H3-K9 acetylation increased in late trophozoite and schizont stages, while H4-K16 acetylation peaked in mid-trophozoite stage. We have also shown that despite the sequence divergence in the PfH3 N-terminus from their mammalian homologues, the recombinant PfH3 was still efficiently acetylated by both recombinant and native PfGCN5 at K9 and K14. This study suggests that histone replacement and the dynamic histone modifications play important roles in regulating gene expression during erythrocytic development of the malaria parasite.

Acetylation↗
PubMed2003

Apoptotic pathways activated by histone deacetylase inhibitors: implications for the drug-resistant phenotype.

Histones are abundant proteins that coordinate the organization of eukaryotic nucleosomes. Post-translational modifications of histones-acetylation, phosphorylation and methylation-locally modulate the higher order nucleosome structure. Acetylation and deacetylation of histones occur at their N-terminal tails in a dynamic fashion and influence DNA accessibility to factors regulating replication, repair and transcription. Acetylation, catalyzed by histone acetyltransferases (HATs) on the epsilon-NH(2) group of lysine residues, neutralizes the positive charge and thereby triggers transcriptional activation. Deacetylation, catalyzed by histone deacetylases (HDACs) on the same lysine residues, unmasks the charge and triggers transcriptional repression. Inhibition of HDACs has thus a broad effect on chromatin architecture, and possibly on protein function, and multiple effects on cell growth. HDAC inhibitors (HDIs) are promising as single anti-cancer agents and in combination therapies. Understanding of the molecular basis for HDIs action is needed to better design the clinical antitumor treatments. The apoptotic pathways induced by HDIs are emerging and we provide an overview of the recent findings that regard apoptotic key elements. We also propose that transformed cells discern the widespread effect of HDIs on chromatin architecture as a genotoxic insult to respond to through induction of apoptosis.

Animals↗
PubMed2003

Trimethylated lysine 9 of histone H3 is a mark for DNA methylation in Neurospora crassa.

Besides serving to package nuclear DNA, histones carry information in the form of a diverse array of post-translational modifications. Methylation of histones H3 and H4 has been implicated in long-term epigenetic 'memory'. Dimethylation or trimethylation of Lys4 of histone H3 (H3 Lys4) has been found in expressible euchromatin of yeasts and mammals. In contrast, methylation of Lys9 of histone H3 (H3 Lys9) has been implicated in establishing and maintaining the largely quiescent heterochromatin of mammals, yeasts, Drosophila melanogaster and plants. We have previously shown that a DNA methylation mutant of Neurospora crassa, dim-5 (defective in methylation), has a nonsense mutation in the SET domain of an H3-specific histone methyltransferase and that substitutions of H3 Lys9 cause gross hypomethylation of DNA. Similarly, the KRYPTONITE histone methyltransferase is required for full DNA methylation in Arabidopsis thaliana. We used biochemical, genetic and immunological methods to investigate the specific mark for DNA methylation in N. crassa. Here we show that trimethylated H3 Lys9, but not dimethylated H3 Lys9, marks chromatin regions for cytosine methylation and that DIM-5 specifically creates this mark.

DNA Methylation↗
PubMed1976

Activation of chromatin by acetylation of histone side chains.

The ability of calf thymus chromatin to support DNA-dependent RNA synthesis is markedly increased by modification of the histones with acetic anhydride. The extent of chemical acetylation of histones H2a, H2b, H3, and H4 required for the increase of template activity of the chromatin is within that which can be achieved enzymatically in the cell. The evidence suggests that the acetylation of histone side chains stimulates the rate of chain elongation during transcription of chromatin.

Acetylation↗
PubMed2001

Translating the histone code.

Chromatin, the physiological template of all eukaryotic genetic information, is subject to a diverse array of posttranslational modifications that largely impinge on histone amino termini, thereby regulating access to the underlying DNA. Distinct histone amino-terminal modifications can generate synergistic or antagonistic interaction affinities for chromatin-associated proteins, which in turn dictate dynamic transitions between transcriptionally active or transcriptionally silent chromatin states. The combinatorial nature of histone amino-terminal modifications thus reveals a "histone code" that considerably extends the information potential of the genetic code. We propose that this epigenetic marking system represents a fundamental regulatory mechanism that has an impact on most, if not all, chromatin-templated processes, with far-reaching consequences for cell fate decisions and both normal and pathological development.

Acetylation↗
PubMed2003

GABAergic cortical neuron chromatin as a putative target to treat schizophrenia vulnerability.

Inhibitory GABAergic interneurons of prefrontal cortex (PFC) appear to play an important role in the regulation of intermittent pyramidal neuron columnary firing and in the neuronal plasticity that mediate cognitive functions. In schizophrenia (SZ), cognitive defects and dysfunctions in pyramidal neuronal columnary firing appear to depend on abnormalities of GABAergic neurons. These abnormalities include a decrease of GAD67 and reelin expression, which result in a reduction of cortical inhibitory input to spine postsynaptic densities as a result of the decrease of GABA concentration at the synaptic cleft, and of neurotrophic stimuli as a result of the decrease of reelin secreted into the extracellular matrix. Our studies show that alterations in chromatin remodeling related to a selective upregulation of DNA-5-cytosine methyltransferase (DNMT) expression in GABAergic neurons of SZ PFC may induce a hypermethylation of reelin and GAD67 promoter CpG islands, which downregulates their expression. In addition, we report preliminary evidence suggesting that by targeting this chromatin-remodeling deficit with inhibitors of histone deacetylases (HDAC), it may be possible to reduce the DNMT upregulation via a covalent modification of nucleosomal histone tails, underscoring the possibility that by addressing a chromatin remodeling deficit, one may treat psychiatric disorders.

Animals↗