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PubMed2004

Beyond the double helix: writing and reading the histone code.

Chromatin is the physiological carrier of not only genetic information, encoded in the DNA, but also of epigenetic information including DNA methylation and histone modifications. As such histone modifications are involved in many aspects of nuclear processes including gene regulation and chromosome segregation. Recently, a 'histone code' hypothesis was put forward to explain how patterns of histone modification may function in downstream processes. In support of the 'histone code' hypothesis, we found in vivo and in vitro evidence that effector proteins, HP1 (heterochromatin protein 1) and Pc (Polycomb) can discriminate and 'read' histone methylation marks on K9 and K27, respectively. Moreover, we propose a 'binary switch' model and suggest that binding and release of effector proteins to their cognate sites can be regulated by modifications on adjacent or nearby residues. Thus, combinations of adjacent histone modifications would function differently from singular modification, and static modifications (e.g. Lys methylation) may well be regulated by dynamic modifications (e.g. phosphorylation). Finally, we describe a novel histone phosphorylation event linking the function of Mst1 kinase and H2B Ser14 phosphorylation with apoptotic chromatin condensation in vertebrates. As this modification is not found during mitotic chromosome condensation, these findings suggest the intriguing possibility that a unique 'death' mark exists for chromatin condensation during apoptosis.

Acetylation↗

PubMed2005

Do protein motifs read the histone code?

The existence of different patterns of chemical modifications (acetylation, methylation, phosphorylation, ubiquitination and ADP-ribosylation) of the histone tails led, some years ago, to the histone code hypothesis. According to this hypothesis, these modifications would provide binding sites for proteins that can change the chromatin state to either active or repressed. Interestingly, some protein domains present in histone-modifying enzymes are known to interact with these covalent marks in the histone tails. This was first shown for the bromodomain, which was found to interact selectively with acetylated lysines at the histone tails. More recently, it has been described that the chromodomain can be targeted to methylation marks in histone N-terminal domains. Finally, the interaction between the SANT domain and histones is also well documented. Overall, experimental evidence suggests that these domains could be involved in the recruitment of histone-modifying enzymes to discrete chromosomal locations, and/or in the regulation their enzymatic activity. Within this context, we review the distribution of bromodomains, chromodomains and SANT domains among chromatin-modifying enzymes and discuss how they can contribute to the translation of the histone code.

Adenosine Triphosphate↗

PubMed2000

Retrovirus vector silencing is de novo methylase independent and marked by a repressive histone code.

Retrovirus vectors are de novo methylated and transcriptionally silent in mammalian stem cells. Here, we identify epigenetic modifications that mark retrovirus-silenced transgenes. We show that murine stem cell virus (MSCV) and human immunodeficiency virus type 1 (HIV-1) vectors dominantly silence a linked locus control region (LCR) beta-globin reporter gene in transgenic mice. MSCV silencing blocks LCR hypersensitive site formation, and silent transgene chromatin is marked differentially by a histone code composed of abundant linker histone H1, deacetylated H3 and acetylated H4. Retrovirus-transduced embryonic stem (ES) cells are silenced predominantly 3 days post-infection, with a small subset expressing enhanced green fluorescent protein to low levels, and silencing is not relieved in de novo methylase-null [dnmt3a-/-;dnmt3b-/-] ES cells. MSCV and HIV-1 sequences also repress reporter transgene expression in Drosophila, demonstrating establishment of silencing in the absence of de novo and maintenance methylases. These findings provide mechanistic insight into a conserved gene silencing mechanism that is de novo methylase independent and that epigenetically marks retrovirus chromatin with a repressive histone code.

Animals↗

PubMed2003

Histone deacetylases: unique players in shaping the epigenetic histone code.

The epigenome is defined by DNA methylation patterns and the associated posttranslational modifications of histones. This histone code determines the expression status of individual genes dependent upon their localization on the chromatin. The silencing of gene expression is associated with deacetylated histones, which are often found to be associated with regions of DNA methylation as well as methylation at the lysine 4 residue of histone 3. In contrast, the activation of gene expression is associated with acetylated histones and methylation at the lysine 9 residue of histone 3. The histone deactylases play a major role in keeping the balance between the acetylated and deacetylated states of chromatin. Histone deacetylases (HDACs) are divided into three classes: class I HDACs (HDACs 1, 2, 3, and 8) are similar to the yeast RPD3 protein and localize to the nucleus; class II HDACs (HDACs 4, 5, 6, 7, 9, and 10) are homologous to the yeast HDA1 protein and are found in both the nucleus and cytoplasm; and class III HDACs form a structurally distinct class of NAD-dependent enzymes that are similar to the yeast SIR2 proteins. Since inappropriate silencing of critical genes can result in one or both hits of tumor suppressor gene (TSG) inactivation in cancer, theoretically the reactivation of affected TSGs could have an enormous therapeutic value in preventing and treating cancer. Indeed, several HDAC inhibitors are currently being developed and tested for their potency in cancer chemotherapy. Importantly, these agents are also potentially applicable to chemoprevention if their toxicity can be minimized. Despite the toxic side effects and lack of specificity of some of the inhibitors, progress is being made. With the elucidation of the structures, functions and modes of action of HDACs, finding agents that may be targeted to specific HDACs and potentially reactivate expression of only a defined set of affected genes in cancer will be more attainable.

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↗

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↗

PubMed2004

Bromodomains in living cells participate in deciphering the histone code.

Explore the source record for details and available documents.

Acetylation↗

PubMed2003

The histone code regulating expression of the imprinted mouse Igf2r gene.

The mouse IGF-II receptor (Igf2r) and its antisense transcript Air are reciprocally imprinted in most normal tissues. Several mechanisms have been hypothesized to explain Igf2r-Air imprinting, including Igf2r silencing by Air, and transcriptional repression of Igf2r-Air by two differentially methylated regions (DMR1 and DMR2). We employed Mus musculus x Mus spretus interspecific mice and chromatin immunoprecipitation (ChIP) to investigate allele-specific histone modifications in the two DMRs. We show that, in both DMRs, the active alleles of both Igf2r, and Air are associated with acetylated histones (H3, and H4), acetyl lysine 9 of histone H3 (H3 K9-Ac), and methyl lysine 4 of histone H3 (H3 K4-Me). The silenced alleles are associated with methylated DNA, deacetylated H3 K9, and unmethylated H3 K4. Allele-specific histone modifications are present in the DMR2 that is established in the gametes and represents the DNA gametic-imprint of the Igf2r. In the DMR2 from liver, kidney, and central nervous system tissues, H3 K9 methylation is associated exclusively with the silenced allele, and H3 S10 phosphorylation with the active alleles. Treatment of fibroblast cells with 5-aza-deoxycytidine and/or Trichostatin A led to partial reactivation of the silenced allele, which correlates with biallelic histone acetylation. In central nervous system, despite the presence of imprinted Air transcripts, biallelic expression of Igf2r occurs. The tissue-specific relaxation of Igf2r imprinting correlates with biallelic histone acetylation, and biallelic H3 K4 methylation in the promoter region of Igf2r (DMR1). We propose a model of the histone code for Igf2r, and Air imprinting that defines histone modifications specific for the putative gametic imprint DMR2, and explains the tissue-specific imprinting of Igf2r in the mouse and the absence of IGF2R imprinting in human.

Acetylation↗

PubMed2024

On the Hunt for the Histone Code.

Our genome is not made of naked DNA but a fiber (chromatin) composed of DNA and proteins packaged into our chromosomes. The basic building block of chromatin is the nucleosome, which has two copies of each of the proteins called histones (H2A, H2B, H3, and H4) wrapped by 146 base pairs of DNA. Regions of our genetic material are found between the more open (euchromatin) and more compact (heterochromatin) regions of the genome that can be variably accessible to the underlying genes. Furthermore, post-translational modifications (PTMs) on histones, such as on H3, are critical for regulating chromatin accessibility and gene expression. While site-specific antibodies were the tool of choice for histone PTM analysis in the early days (pre-2000s), enter Don Hunt changing the histone PTM field forever. Don's clever thinking brought new innovative mass spectrometry-based approaches to the epigenetics field. His lab's effort led to the discovery of many new histone modifications and methods to facilitate the detection and quantification of histone PTMs, which are still considered state of the art in the proteomics field today. Due to Don's pioneering work in this area, many labs have been able to jump into the epigenetics field and "Hunt" down their own histone targets. A walkthrough of those early histone years in the Hunt Lab is described by three of us who were fortunate enough to be at the right place, at the right time.

Animals↗

PubMed2003

Resetting the histone code at CDKN2A in HNSCC by inhibition of DNA methylation.

Head and neck squamous cell carcinoma (HNSCC) is the fifth most frequent cancer in the US. Several genetic and epigenetic alterations are associated with HNSCC tumorigenesis, including inactivation of CDKN2A, which encodes the p16 tumor suppressor, in cell lines and primary tumors by DNA methylation. Reactivation of tumor suppressor genes by DNA-demethylating agents and histone deacetylase (HDAC) inhibitors shows therapeutic promise for other cancers. Therefore, we investigated the ability of these agents to reactivate p16 in Tu159 HNSCC cells. Treatment of cells with 5-aza-2'deoxycytidine (5-aza-dC) increases CDKN2A expression and slightly increases histone H3 acetylation at this gene. No reactivation of CDKN2A is observed upon treatment with the HDAC inhibitor trichostatin A (TSA), but synergistic reactivation of CDKN2A is observed upon sequential treatment of Tu159 cells with both 5-aza-dC and TSA. Silencing of CDKN2A in Tu159 cells is correlated with increased methylation of histone H3 at lysine 9 and decreased methylation at lysine 4 relative to the upstream p15 gene promoter. Interestingly, global levels of H3-K9 methylation are decreased upon treatment with 5-aza-dC. Together these data indicate that DNA methylation is a dominant epigenetic mark for silencing of CDKN2A in Tu159 tumor cells. Moreover, changes in DNA methylation can reset the histone code by impacting multiple H3 modifications.

Animals↗

PubMed2004

Promoter-restricted histone code, not the differentially methylated DNA regions or antisense transcripts, marks the imprinting status of IGF2R in human and mouse.

Imprinting of the mouse Igf2r depends upon an intronic differentially methylated DNA region (DMR) and the presence of the Air antisense transcript. However, biallelic expression of mouse Igf2r in brain occurs despite the presence of Air, and biallelic expression of human IGF2R in peripheral tissues occurs despite the presence of an intronic DMR. We examined histone modifications throughout the mouse and human Igf2r/IGF2R using chromatin immuno-precipitation (ChIP) assays in combination with quantitative real time PCR. Methylation of Lys4 and Lys9 of histone H3 in the promoter regions marks the active and silenced alleles, respectively. We measured di- and tri-methyl Lys4 and Lys9 across the Igf2r and Air promoters. While both di- and tri-methyl Lys4 marked the active Igf2r and the active Air allele, tri-methyl Lys9, but not di-methyl Lys9, marked the suppressed Air allele. We show here that enrichment of parental allele-specific histone modifications in the promoter region, rather than the presence of DNA methylation or antisense transcription, correctly identifies the tissue- and species- specific imprinting status of Igf2r/IGF2R. We discuss these findings in light of recent progress in identifying specific components of the epigenetic marks in imprinted genes.

Acetylation↗

PubMed2005

Chromatin modifier enzymes, the histone code and cancer.

In all organisms, cell proliferation is orchestrated by coordinated patterns of gene expression. Transcription results from the activity of the RNA polymerase machinery and depends on the ability of transcription activators and repressors to access chromatin at specific promoters. During the last decades, increasing evidence supports aberrant transcription regulation as contributing to the development of human cancers. In fact, transcription regulatory proteins are often identified in oncogenic chromosomal rearrangements and are overexpressed in a variety of malignancies. Most transcription regulators are large proteins, containing multiple structural and functional domains some with enzymatic activity. These activities modify the structure of the chromatin, occluding certain DNA regions and exposing others for interaction with the transcription machinery. Thus, chromatin modifiers represent an additional level of transcription regulation. In this review we focus on several families of transcription activators and repressors that catalyse histone post-translational modifications (acetylation, methylation, phosphorylation, ubiquitination and SUMOylation); and how these enzymatic activities might alter the correct cell proliferation program, leading to cancer.

Acetylation↗

PubMed1976

Histone genes of the sea urchin (S. purpuratus) cloned in E coli: order, polarity, and strandedness of the five histone-coding and spacer regions.

Sea urchin (S. purpuratus) histone DNA of constructed plasmid chimeras cloned in E. coli was cleaved with the restriction endonucleases Eco RI, Hind III, Sal I. Bam I, and Hha I. The resulting fragments were ordered and isolated directly from agarose gels or cloned into other plasmids. Each fragment hybridized to one or another of the five histone mRNAs and elucidated the order of the histone genes in each of the cloned fragments. Some DNA did not hybridize to histone mRNAs and was identified as spacer DNA located between coding regions. Total sea urchin DNA was cleaved with restriction endonucleases, fractionated on agarose gels, and hybridized to histone mRNAs or histone DNA. The results revealed the order of the five histone genes in the histone gene repeat unit and demonstrate that the histone spacer DNA have little sequence homology to other genes. ExonucleaseIII digestion of specific linear chimeric histone DNA plasmids followed by hybridization with mRNAs demonstrated the existence of all five histone genes on one strand of DNA and the 5'-3' polarity of that strand. These results, in conjunction with the data of Wu et al. (1976), allow us to construct a map of coding and spacer sequences in the transcribed strand of S. purpuratus histone gene repeat unit: (see article).

Animals↗

PubMed2006

For a healthy histone code, a little SUMO in the tail keeps the acetyl away.

Chemical modification of histones through a growing number of post-translational mechanisms is an integral part of transcription. A recent report provides exciting new evidence that conjugation of the ubiquitin-like protein SUMO to histones opposes acetylation and establishes SUMOylation as an important histone mark linked to transcriptional repression.

Acetylation↗

PubMed2003

Cracking the histone code: one, two, three methyls, you're out!

In this issue of Molecular Cell, Zhang et al. report the structure of a ternary complex between the SET domain histone methyltransferase DIM-5, its cofactor, and a histone H3 peptide. The insight gained from analysis of a key amino acid provides an exciting opportunity to dissect the possible functional meaning of mono-, di-, and trimethylation of histone lysine residues in vivo that will complement existing approaches in the quest to crack the histone methylation code.

Amino Acid Sequence↗

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↗

PubMed2005

The expression of endothelial nitric-oxide synthase is controlled by a cell-specific histone code.

Expression of endothelial nitric-oxide synthase (eNOS) mRNA is highly restricted to the endothelial cell layer of medium to large sized arterial blood vessels. Here we assessed the chromatin environment of the eNOS gene in expressing and nonexpressing cell types. Within endothelial cells, but not a variety of nonendothelial cells, the nucleosomes that encompassed the eNOS core promoter and proximal downstream coding regions were highly enriched in acetylated histones H3 and H4 and methylated lysine 4 of histone H3. This differentially modified chromatin domain was selectively associated with functionally competent RNA polymerase II complexes. Endothelial cells were particularly enriched in acetylated histone H3 lysine 9, histone H4 lysine 12, and di- and tri-methylated lysine 4 of histone H3 at the core promoter. Histone modifications at this region, which we have previously demonstrated to exhibit cell-specific DNA methylation, were functionally relevant to eNOS expression. Inhibition of histone deacetylase activity by trichostatin A increased acetylation of histones H3 and H4 at the eNOS proximal promoter in nonexpressing cell types and led to increased steady-state eNOS mRNA transcript levels. H3 lysine 4 methylation was also essential for eNOS expression, since treatment of endothelial cells with methylthioadenosine, a known lysine 4 methylation inhibitor, decreased eNOS RNA levels, H3 lysine 4 methylation, and RNA polymerase II loading at the eNOS proximal promoter. Importantly, methylthioadenosine also prevented the trichostatin A-mediated increase in eNOS mRNA transcript levels in nonendothelial cells. Taken together, these findings provide strong evidence that the endothelial cell-specific expression of eNOS is controlled by cell-specific histone modifications.

Acetylation↗

PubMed1978

The DNA sequence of sea urchin (S. purpuratus) H2A, H2B and H3 histone coding and spacer regions.

The DNA sequence of two cloned segments of the histone gene repeat unit of the sea urchin S. purpuratus has been determined. One sequence contains the contiguous H2B and H3 genes and their interdigitated spacer regions; the other comprises the H2A gene and flanking spacer sequences. Analysis of the coding regions reveals a methionine residue within the H2A protein. H2A, which generally lacks this amino acid, contains methionine only in a protein variant which is synthesized in early sea urchin embryogenesis. We thus conclude that the cloned DNA represents a set of genes which is active early in development. Codon selection is markedly skewed and similar for each of the three genes. The DNA sequences are co-linear with known histone protein sequences and-unlike several other eucaryotic genes-do not show any insertions in the coding regions. The spacer regions are relatively AT-rich although GC cluster are scattered throughout. Several short stretches of homology are found in regions both upstream and downstream from the protein coding segments. The conservation of these sequences and their location at analogous sites suggest that they are involved in gene transcription or in mRNA translation. No tandem or dispersed repeats were found, with the exception of the remarkable sequence having the structure located in the spacer between the H2A and H1 genes.

Animals↗