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PubMed1985

Giant readthrough transcription units at the histone loci on lampbrush chromosomes of the newt Notophthalmus.

We have studied transcription at the histone loci in oocytes of the newt Notophthalmus viridescens, using in situ hybridization of cloned probes to the nascent RNA on lampbrush chromosome loops. Clusters of the five histone coding sequences are separated by long tracts of a simple sequence DNA, satellite 1. We had previously demonstrated coordinate transcription of histone genes and satellite 1 sequences. We postulated that satellite sequences were transcribed by readthrough from histone gene promoters; that is, transcription initiated at any of the five usual promoters, but did not terminate at the 3' end of the gene. Instead transcription proceeded through downstream sequences in the histone cluster (including spacers and downstream histone genes), and then through the satellite 1 region. Our model led to several specific predictions, in particular that some internal spacer regions between the genes should be well represented in the RNA on loops, that certain sequences should be absent from the loops, and that presence or absence of particular sequences should be correlated with morphological polarity of the transcription unit. We have hybridized ten strand-specific probes to the lamp-brush chromosomes and we find that the patterns of hybridization agree with the readthrough model of transcription.

Animals↗
PubMed2004

Proteasomal ATPases link ubiquitylation of histone H2B to methylation of histone H3.

In Saccharomyces cerevisiae, methylation of histone H3 at active genes is an epigenetic mark that distinguishes active from silent chromatin and functions as a short-term "memory" of recent transcription. Methylation of H3 at lysine residues K4 and K79 depends on ubiquitylation of histone H2B, but the mechanisms linking H2B ubiquitylation to H3 methylation are unknown. Here, we demonstrate that proteasomal ATPases Rpt4 and Rpt6 function to connect these two histone modifications. We show that recruitment of proteasome subunits to chromatin depends on H2B ubiquitylation and that mutations in Rpt4 and Rpt6 disrupt H3 methylation at K4 and K79 but leave H2B ubiquitylation intact. Consistent with their role in H3 methylation, we also find that mutations in Rpt4 and 6-but not components of the 20S proteasome-disrupt telomeric gene silencing. These data reveal that proteasome subunits function in epigenetic gene regulation by linking chromatin modifications that establish the histone code.

Adenosine Triphosphatases↗
PubMed2005

Novel phosphorylation of histone H3 at threonine 11 that temporally correlates with condensation of mitotic and meiotic chromosomes in plant cells.

A novel mitosis-specific phosphorylation site in histone H3 at threonine 11 has been described for mammalian cells. This modification is restricted to the centromeric region while phosphorylation at the classical H3 sites, Ser10 and Ser28 occurs along the entire chromosomal arms. Using phosphorylation state-specific antibodies we found that phosphorylation at threonine 11 occurs also in plant cells, during mitosis as well as meiosis. However, in contrast to animal cells, ph(Thr11)H3 was distributed along the entire length of condensed chromosomes, whereas H3 phosphorylated at Ser10 and Ser28 appeared to be restricted to centromeric/pericentromeric chromatin. Phosphorylation at Thr11 started in prophase and ended in telophase, it correlated with the condensation of mitotic and meiotic chromosomes and was independent of the distribution of late replicating heterochromatin and Giemsa-banding positive regions. Interestingly, treatment of cells with the phosphatase inhibitor cantharidin revealed a high level of Thr11 phosphorylation in interphase cells, in this case particularly in pericentromeric regions. These data show that histone modifications are highly dynamic. Moreover, animal and plant organisms may have evolved individual histone codes.

Arabidopsis↗
PubMed2006

Regulating chromatin: on code and dynamic models.

In this short comment on the contributions by Arndt Benecke, Francois Fuks and Helmut Schiessel I refer to some recent experimental work which sheds light on the histone code hypothesis. Further, I make some remarks on the role theoretical approaches can play in decoding chromatin regulation.

Genetic Code↗
PubMed2004

A mass spectrometric "Western blot" to evaluate the correlations between histone methylation and histone acetylation.

Histone acetylation, methylation, and phosphorylation occur predominantly in the unstructured N-terminal domains or histone "tails". These modifications and others comprise a "histone code" that directly facilitates or antagonizes association of regulatory proteins with nucleosomes to mediate changes in chromatin structure and activity. Methylation of histone H3 outside of the tail region at lysine 79 has been reported for a variety of species ranging from yeast to humans and in some gene-specific cases appears to be associated with active chromatin and transcription. Whether methylation of lysine 79 is associated with other post-translational modifications of the H3 tail is unknown. Using mass spectrometric relative quantitation, a mass spectrometric "Western blot", we compare methylation at lysines 4, 9, and 79 with acetylation of human histone H3. We find that the total levels of lysine 4 and 79 methylation (combined mono-, di-, and trimethylation) in the H3 population increase with the degree of H3 tail acetylation. The total amount of lysine 4 methylation increases progressively from less than 10% in the nonacetylated H3 to greater than 90% in the penta-acetylated H3. In addition, significant levels of lysine 4 trimethylation also occur in combination with the penta-acetylated H3 species. In contrast, the level of H3 lysine 9 trimethylation is greatest for the monoacetylated species while H3 lysine 9 acetylation occurs predominantly in hyperacetylated (tetra- and penta-acetylated) H3 isoforms. Together, these results indicate that methylation of lysine 4 and 79 as well as the switch from lysine 9 methylation to acetylation are coordinated synchronously with H3 hyperacetylation as marks of active chromatin.

Acetic Acid↗
PubMedDate not supplied

Epigenetic changes in colorectal cancer.

Epigenetic silencing is now recognized as a 'third pathway' in Knudson's model of tumor-suppressor gene inactivation in cancer and can affect gene function without genetic changes. DNA methylation within gene promoters and alterations in histone modifications appear to be primary mediators of epigenetic inheritance in cancer cells. For selected genes, epigenetic changes are tightly related to neoplastic transformation in colorectal cancers (CRCs). In the colon, aberrant DNA methylation arises very early, initially in normal appearing mucosa, and may be part of the age-related field defect observed in sporadic CRCs. Aberrant methylation also contributes to later stages of colon cancer formation and progression through a hypermethylator phenotype termed CpG Island Methylator Phenotype (CIMP), which appears to be a defining event in about half of all sporadic tumors. CIMP+ CRCs are distinctly characterized by pathology, clinical and molecular genetic features. Histone modifications, recently recognized as a 'histone code' that affects chromatin structure and gene expression also play an important role in the establishment of gene silencing during tumorigenesis. DNA methylation and histone H3 lysine 9 hypoacetylation and methylation appear to form a mutually reinforcing silencing loop that contributes to tumor-suppressor gene inactivation in CRCs. Understanding epigenetic alterations as a driving force in neoplasia opens new fields of research in epidemiology, risk assessment, and treatment in CRCs.

Chromatin↗
PubMed2001

Re-SET-ting heterochromatin by histone methyltransferases.

Histone methylation was first described more than 35 years ago, but its role has remained enigmatic. Proposed functions range from transcriptional regulation to the higher-order packaging of chromatin in preparation for mitotic condensation. Histone methylation can occur on Arg or Lys residues, with an exquisite site selectivity for Lys methylation at specific positions in the N-termini of histones H3 and H4. Thus, Lys methylation joins acetylation and phosphorylation as a third component of a 'histone code' that modifies the underlying chromatin structure of the genetic information. Notably, in contrast to acetylation and phosphorylation, Lys methylation appears to be a relatively stable histone modification, thereby providing an ideal epigenetic mark for more long-term maintenance of chromatin states. The recent discovery of the first histone Lys methyltransferase has allowed the identification of a molecular mechanism in which the specific methylation of histone H3 at Lys9 generates a binding site for heterochromatin-associated proteins. These findings have broad implications for the overall functional organization of chromosome structure at constitutive heterochromatin (e.g. centromeres) and for chromatin-dependent inheritance of gene expression patterns. This review discusses how understanding this methylation system should address some of the long-standing mysteries of heterochromatin.

Amino Acid Sequence↗
PubMed2003

Identification of methylation and acetylation sites on mouse histone H3 using matrix-assisted laser desorption/ionization time-of-flight and nanoelectrospray ionization tandem mass spectrometry.

Covalent modifications to histone proteins are well documented in the literature. Specific modification sites are correlated with chromatin structure and transcriptional activity. The histone code is very complex, and includes several types of covalent modifications such as acetylation, methylation, phosphorylation, and ubiquitination of at least 20 possible sites within the histone proteins. The final chromatin structure "read-out" is a result of the cooperation between these many sites of covalent modifications. Methylation and acetylation sites of histone H3 from many different species have been previously identified. However, a full post-translational modification status on histone H3 from mouse has not yet been reported. Here we demonstrate the use of high-accuracy matrix-assisted laser desorption/ionization time-of-flight and nanoelectrospray ionization tandem mass spectrometry to identify the methylation and acetylation sites of the mouse histone H3. In addition to the sites previously identified from other species, one unique methylation site, Lys-122, from mouse histone H3 was identified. The reported mass spectrometric method provides an efficient and sensitive way for analyzing post-translational modifications of histone proteins.

Acetylation↗
PubMed2003

mSin3-associated protein, mSds3, is essential for pericentric heterochromatin formation and chromosome segregation in mammalian cells.

The histone code guides many aspects of chromosome biology including the equal distribution of chromosomes during cell division. In the chromatin domains surrounding the centromere, known as pericentric heterochromatin, histone modifications, particularly deacetylation and methylation, appear to be essential for proper chromosome segregation. However, the specific factors and their precise roles in this highly orchestrated process remain under active investigation. Here, we report that germ-line or somatic deletion of mSds3, an essential component of the functional mSin3/HDAC corepressor complex, generates a cell-lethal condition associated with rampant aneuploidy, defective karyokinesis, and consequently, a failure of cytokinesis. mSds3-deficient cells fail to deacetylate and methylate pericentric heterochromatin histones and to recruit essential heterochromatin-associated proteins, resulting in aberrant associations among heterologous chromosomes via centromeric regions and consequent failure to properly segregate chromosomes. Mutant mSds3 molecules that are defective in mSin3 binding fail to rescue the mSds3 null phenotypes. On the basis of these findings, we propose that mSds3 and its associated mSin3/HDAC components play a central role in initiating the cascade of pericentric heterochromatin-specific modifications necessary for the proper distribution of chromosomes during cell division in mammalian cells.

Acetylation↗
PubMed2005

Relationship between histone H3 lysine 9 methylation, transcription repression, and heterochromatin protein 1 recruitment.

Histone H3 lysine 9 (H3-K9) methylation has been shown to correlate with transcriptional repression and serve as a specific binding site for heterochromatin protein 1 (HP1). In this study, we investigated the relationship between H3-K9 methylation, transcriptional repression, and HP1 recruitment by comparing the effects of tethering two H3-K9-specific histone methyltransferases, SUV39H1 and G9a, to chromatin on transcription and HP1 recruitment. Although both SUV39H1 and G9a induced H3-K9 methylation and repressed transcription, only SUV39H1 was able to recruit HP1 to chromatin. Targeting HP1 to chromatin required not only K9 methylation but also a direct protein-protein interaction between SUV39H1 and HP1. Targeting methyl-K9 or a HP1-interacting region of SUV39H1 alone to chromatin was not sufficient to recruit HP1. We also demonstrate that methyl-K9 can suppress transcription independently of HP1 through a mechanism involving histone deacetylation. In an effort to understand how H3-K9 methylation led to histone deacetylation in both H3 and H4, we found that H3-K9 methylation inhibited histone acetylation by p300 but not its association with chromatin. Collectively, these data indicate that H3-K9 methylation alone can suppress transcription but is insufficient for HP1 recruitment in the context of chromatin exemplifying the importance of chromatin-associated factors in reading the histone code.

Acetylation↗
PubMed1986

Human histone genes map to multiple chromosomes.

Histone genes were mapped to at least three human chromosomes by Southern blot analysis of DNAs from a series of mouse-human somatic cell hybrids (using 32P-labeled cloned human histone DNA as probes). Chromosome assignment was confirmed by in situ hybridization of radiolabeled histone gene probes (3H-labeled) to metaphase chromosomes. One human histone gene cluster (lambda HHG41) containing an H3 and H4 gene resides only on chromosome 1, whereas other clusters containing core (H3, H4, H2A, and H2B) alone (lambda HHG17) or core together with H1 histone genes (lambda HHG415) have been assigned to chromosomes 1, 6, and 12. These results suggest that the multigene family of histone coding sequences that reside in a series of clusters may be derived from a single cluster containing one each of the genes for the five principal classes of histone proteins. During the course of evolution, a set of events, probably involving reduplication, sequence modification, and recombination, resulted in the present pattern of human histone gene distribution among several chromosomes.

Biological Evolution↗
PubMed2006

HP1 proteins are essential for a dynamic nuclear response that rescues the function of perturbed heterochromatin in primary human cells.

Cellular information is encoded genetically in the DNA nucleotide sequence and epigenetically by the "histone code," DNA methylation, and higher-order packaging of DNA into chromatin. Cells possess intricate mechanisms to sense and repair damage to DNA and the genetic code. However, nothing is known of the mechanisms, if any, that repair and/or compensate for damage to epigenetically encoded information, predicted to result from perturbation of DNA and histone modifications or other changes in chromatin structure. Here we show that primary human cells respond to a variety of small molecules that perturb DNA and histone modifications by recruiting HP1 proteins to sites of altered pericentromeric heterochromatin. This response is essential to maintain the HP1-binding kinetochore protein hMis12 at kinetochores and to suppress catastrophic mitotic defects. Recruitment of HP1 proteins to pericentromeres depends on histone H3.3 variant deposition, mediated by the HIRA histone chaperone. These data indicate that defects in pericentromeric epigenetic heterochromatin modifications initiate a dynamic HP1-dependent response that rescues pericentromeric heterochromatin function and is essential for viable progression through mitosis.

Cell Cycle Proteins↗
PubMed2002

Ubiquitination of histone H2B regulates H3 methylation and gene silencing in yeast.

In eukaryotes, the DNA of the genome is packaged with histone proteins to form nucleosomal filaments, which are, in turn, folded into a series of less well understood chromatin structures. Post-translational modifications of histone tail domains modulate chromatin structure and gene expression. Of these, histone ubiquitination is poorly understood. Here we show that the ubiquitin-conjugating enzyme Rad6 (Ubc2) mediates methylation of histone H3 at lysine 4 (Lys 4) through ubiquitination of H2B at Lys 123 in yeast (Saccharomyces cerevisiae). Moreover, H3 (Lys 4) methylation is abolished in the H2B-K123R mutant, whereas H3-K4R retains H2B (Lys 123) ubiquitination. These data indicate a unidirectional regulatory pathway in which ubiquitination of H2B (Lys 123) is a prerequisite for H3 (Lys 4) methylation. We also show that an H2B-K123R mutation perturbs silencing at the telomere, providing functional links between Rad6-mediated H2B (Lys 123) ubiquitination, Set1-mediated H3 (Lys 4) methylation, and transcriptional silencing. Thus, these data reveal a pathway leading to gene regulation through concerted histone modifications on distinct histone tails. We refer to this as 'trans-tail' regulation of histone modification, a stated prediction of the histone code hypothesis.

Alleles↗
PubMed2002

Structure of the SET domain histone lysine methyltransferase Clr4.

Methylation of histone H3 lysine 9 is an important component of the 'histone code' for heterochromatic gene silencing. The SET domain-containing Clr4 protein, a close relative of Su(var)3-9 proteins in higher eukaryotes, specifically methylates lysine 9 of histone H3 and is essential for silencing in Schizosaccharomyces pombe. Here we report the 2.3 A resolution crystal structure of the catalytic domain of Clr4. The structure reveals an overall fold rich in beta-strands, a potential active site consisting of a SAM-binding pocket, and a connected groove that could accommodate the binding of the N-terminal tail of histone H3. The pre-SET motif contains a triangular zinc cluster coordinated by nine cysteines distant from the active site, whereas the post-SET region is largely flexible but proximal to the active site. The structure provides insights into the architecture of SET domain histone methyltransferases and establishes a paradigm for further characterization of the Clr4 family of epigenetic regulators.

Amino Acid Sequence↗
PubMed2005

X box-like sequences in the MHC class II region maintain regulatory function.

Sequences homologous to the canonical MHC class II (MHC-II) gene X box regulatory elements were identified within the HLA-DR subregion of the human MHC and termed X box-like (XL) sequences. Several XL box sequences were found to bind the MHC class II-specific transcription factors regulatory factor X and CIITA and were transcriptionally active. The histone code associated with the XL boxes and that of the HLA-DRA X box was determined. Using CIITA-positive and -negative B cell lines, CIITA-specific histone modifications were identified and found to be consistent among the active XL boxes. Although a remarkable similarity was observed for most modifications, differences in magnitude between the HLA-DRA promoter for modifications associated with the assembly of the general transcription factors, such as histone H3 lysine 9 acetylation and H3 lysine 4 trimethylation, distinguished the very active HLA-DRA promoter from the XL box regions. In response to IFN-gamma, XL box-containing histones displayed increased acetylation, coincident with CIITA expression and that observed in B cells, suggesting that the end point mechanisms of chromatin remodeling for cell type-specific MHC-II expression were similar. Lastly, an interaction between one XL box and the HLA-DRA promoter was observed in a chromatin-looping assay. Therefore, these data provide evidence that certain XL box sequences contribute to a global increase in chromatin accessibility of the HLA-DR region in B lymphocytes and in response to IFN-gamma and supports the involvement of these XL sequences in the regulation of MHC-II genes.

Acetylation↗
PubMed2002

Signaling network model of chromatin.

We suggest that common principles underlie both cellular signaling networks and chromatin. To exemplify similarities, we focus on signaling complexes that form at membrane receptors and on nucleosomes. Multiple signal-transducing modifications on side chain residues of receptor tyrosine kinases (RTKs) and histone proteins are used to create docking sites that facilitate proximal relations of enzymes and their substrates. We argue that multiple histone modifications, like RTK modifications, promote switch-like behavior and ensure robustness of the signal, and we compare this interpretation with the histone code hypothesis. This view provides insight into chromatin function and epigenetic inheritance.

Animals↗
PubMed2005

Distinct regulation of histone H3 methylation at lysines 27 and 9 by CpG methylation in Arabidopsis.

Transcriptional activity and structure of chromatin are correlated with patterns of covalent DNA and histone modification. Previous studies have revealed that high levels of histone H3 dimethylation at lysine 9 (H3K9me2), characteristic of transcriptionally silent heterochromatin in Arabidopsis, require hypermethylation of DNA at CpG sites. Here, we report that CpG hypermethylation characteristic of heterochromatin specifically prevented H3K27 trimethylation (H3K27me3). H3K27 mono- and dimethylation mark silent heterochromatin independently of DNA methylation. Upon loss of CpG methylation, there was target-specific enrichment of H3K27me3 in heterochromatin that correlated with transcriptional reactivation. Moreover, using the kyp mutant affected in H3K9me2, we showed that changes in H3K27me3 occurred independently of the levels of H3K9me2. Therefore, CpG methylation provides distinct and direct information for a specific subset of histone methylation marks. The observed independence of the regulation of H3K9 and H3K27 methylation by CpG methylation refines the recently proposed combinatorial histone code involving these two marks.

Arabidopsis↗
PubMed2005

Dynamic DNA methylation and histone modifications contribute to lentiviral transgene silencing in murine embryonic carcinoma cells.

Embryonic stem cells are subjected to a dynamic genome regulation during development. Here we report that the ectopic lentiviral transgenes are quickly silenced in murine embryonic carcinoma P19 cells. The silencing was correlated with CpG hypermethylation in the transgene promoter. Using high-resolution sodium bisulfite genome sequencing, we detected distinct DNA methylation kinetics in different proviral regions. DNase I sensitivity and chromatin immunoprecipitation assays revealed condensed chromatin structure and histone code switch during silencing. Longitudinal analysis of nonsilenced and silenced identical single-cell clones revealed that the silencing was coupled with CpG methylation in the promoter, as well as a global histone H3 deacetylation. Interestingly, the primer binding site and the packaging signal region appeared to serve as a DNA methylation initiation center which was rapidly hypermethylated regardless of transgene silencing and chromatin modifications. Analysis of cellular genes 45 to 50 kbp upstream and downstream of the integration site indicated that transcriptional activities of the flanking host genes were not affected. Genetic modifications of stem cells have great therapeutic potentials and our results picture a dynamic embryonic genome response to ectopic transgene integration that may have important implications in the future safety and efficacy modifications of stem cells.

Animals↗