The language of covalent histone modifications.
TL;DR: It is proposed that distinct histone modifications, on one or more tails, act sequentially or in combination to form a ‘histone code’ that is, read by other proteins to bring about distinct downstream events.
Abstract: Histone proteins and the nucleosomes they form with DNA are the fundamental building blocks of eukaryotic chromatin. A diverse array of post-translational modifications that often occur on tail domains of these proteins has been well documented. Although the function of these highly conserved modifications has remained elusive, converging biochemical and genetic evidence suggests functions in several chromatin-based processes. We propose that distinct histone modifications, on one or more tails, act sequentially or in combination to form a 'histone code' that is, read by other proteins to bring about distinct downstream events.
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TL;DR: It is proposed 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.
Abstract: 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.
9,309 citations
TL;DR: The purification and characterization of an EED-EZH2 complex, the human counterpart of the Drosophila ESC-E(Z) complex, is reported, and it is demonstrated that the complex specifically methylates nucleosomal histone H3 at lysine 27 (H3-K27).
Abstract: Polycomb group (PcG) proteins play important roles in maintaining the silent state of HOX genes. Recent studies have implicated histone methylation in long-term gene silencing. However, a connection between PcG-mediated gene silencing and histone methylation has not been established. Here we report the purification and characterization of an EED-EZH2 complex, the human counterpart of the Drosophila ESC-E(Z) complex. We demonstrate that the complex specifically methylates nucleosomal histone H3 at lysine 27 (H3-K27). Using chromatin immunoprecipitation assays, we show that H3-K27 methylation colocalizes with, and is dependent on, E(Z) binding at an Ultrabithorax (Ubx) Polycomb response element (PRE), and that this methylation correlates with Ubx repression. Methylation on H3-K27 facilitates binding of Polycomb (PC), a component of the PRC1 complex, to histone H3 amino-terminal tail. Thus, these studies establish a link between histone methylation and PcG-mediated gene silencing.
3,565 citations
TL;DR: This Review highlights advances in the understanding of chromatin regulation and discusses how such regulation affects the binding of transcription factors as well as the initiation and elongation steps of transcription.
3,424 citations
Cites background from "The language of covalent histone mo..."
...Given the diversity of covalent modifications, it has been proposed that individual histone modifications or modification patterns might be read by other proteins that influence chromatin dynamics and function (Jenuwein and Allis, 2001; Strahl and Allis, 2000; Turner, 2000)....
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TL;DR: The mechanisms of gene silencing in cancer and clinical applications of this phenomenon are reviewed, especially tumor-suppressor genes.
Abstract: This article reviews the mechanisms of gene silencing in cancer and clinical applications of this phenomenon. The silencing of genes, especially tumor-suppressor genes, is a key event in the development of cancer. The silencing can be effected by a disabling mutation or by a shutting down of the promoter region, the site at which transcription of the gene begins.
3,285 citations
TL;DR: Insight is given into the connections between chromatin modifications and transcriptional regulatory activity and a novel functional enhancer for the carnitine transporter SLC22A5 (OCTN2) is uncovered, providing a new tool for the functional annotation of the human genome.
Abstract: Eukaryotic gene transcription is accompanied by acetylation and methylation of nucleosomes near promoters, but the locations and roles of histone modifications elsewhere in the genome remain unclear. We determined the chromatin modification states in high resolution along 30 Mb of the human genome and found that active promoters are marked by trimethylation of Lys4 of histone H3 (H3K4), whereas enhancers are marked by monomethylation, but not trimethylation, of H3K4. We developed computational algorithms using these distinct chromatin signatures to identify new regulatory elements, predicting over 200 promoters and 400 enhancers within the 30-Mb region. This approach accurately predicted the location and function of independently identified regulatory elements with high sensitivity and specificity and uncovered a novel functional enhancer for the carnitine transporter SLC22A5 (OCTN2). Our results give insight into the connections between chromatin modifications and transcriptional regulatory activity and provide a new tool for the functional annotation of the human genome.
3,215 citations
Cites background from "The language of covalent histone mo..."
...Significant progress in the fields of epigenetics and chromatin biology suggests a histone cod...
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References
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TL;DR: The X-ray crystal structure of the nucleosome core particle of chromatin shows in atomic detail how the histone protein octamer is assembled and how 146 base pairs of DNA are organized into a superhelix around it.
Abstract: The X-ray crystal structure of the nucleosome core particle of chromatin shows in atomic detail how the histone protein octamer is assembled and how 146 base pairs of DNA are organized into a superhelix around it. Both histone/histone and histone/DNA interactions depend on the histone fold domains and additional, well ordered structure elements extending from this motif. Histone amino-terminal tails pass over and between the gyres of the DNA superhelix to contact neighbouring particles. The lack of uniformity between multiple histone/DNA-binding sites causes the DNA to deviate from ideal superhelix geometry.
7,841 citations
TL;DR: The amino termini of histones extend from the nucleosomal core and are modified by acetyltransferases and deacetylases during the cell cycle, which may direct histone assembly and help regulate the unfolding and activity of genes.
Abstract: 'The amino termini of histones extend from the nucleosomal core and are modified by acetyltransferases and deacetylases during the cell cycle These acetylation patterns may direct histone assembly and help regulate the unfolding and activity of genes
2,846 citations
"The language of covalent histone mo..." refers background in this paper
...However, many of the concepts presented here are likely to apply to all of the histone termini and, in particular, to that of histone H...
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TL;DR: This work highlights conserved protein domains that act as key regulatory participants in many of these different signalling pathways in multicellular organisms.
Abstract: Communication between cells assumes particular importance in multicellular organisms. The growth, migration and differentiation of cells in the embryo, and their organization into specific tissues, depend on signals transmitted from one cell to another. In the adult, cell signalling orchestrates normal cellular behaviour and responses to wounding and infection. The consequences of breakdowns in this signalling underlie cancer, diabetes and disorders of the immune and cardiovascular systems. Conserved protein domains that act as key regulatory participants in many of these different signalling pathways are highlighted.
2,433 citations
"The language of covalent histone mo..." refers background in this paper
...Phosphorylated tyrosine, for example, is known to be read in specific contexts by SH2-containing modules that, in turn, have an impact on downstream biological event...
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TL;DR: It is proposed that the singular phosphorylation of the amino-terminus of histone H3 may be involved in facilitating two key functions during mitosis: (1) regulate protein-protein interactions to promote binding of trans-acting factors that “drive” chromatin condensation as cells enter M-phase and (2) coordinate chromatin decondensation associated with M- phase.
Abstract: We have generated and characterized a novel site-specific antibody highly specific for the phosphorylated form of the amino-terminus of histone H3 (Ser10). In this study, we used this antibody to examine in detail the relationship between H3 phosphorylation and mitotic chromosome condensation in mammalian cells. Our results extend previous biochemical studies by demonstrating that mitotic phosphorylation of H3 initiates nonrandomly in pericentromeric heterochromatin in late G2 interphase cells. Following initiation, H3 phosphorylation appears to spread throughout the condensing chromatin and is complete in most cell lines just prior to the formation of prophase chromosomes, in which a phosphorylated, but nonmitotic, chromosomal organization is observed. In general, there is a precise spatial and temporal correlation between H3 phosphorylation and initial stages of chromatin condensation. Dephosphorylation of H3 begins in anaphase and is complete immediately prior to detectable chromosome decondensation in telophase cells. We propose that the singular phosphorylation of the amino-terminus of histone H3 may be involved in facilitating two key functions during mitosis: (1) regulate protein-protein interactions to promote binding of trans-acting factors that "drive" chromatin condensation as cells enter M-phase and (2) coordinate chromatin decondensation associated with M-phase.
1,852 citations
"The language of covalent histone mo..." refers background in this paper
...H3 phosphorylation at serine 10, possibly in conjunction with phosphorylation at serine 28 ( Figs 1b and 2 ; and see below), is also required for proper segregation and condensation of chromosomes during mitosis and meiosi...
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TL;DR: Understanding of the causal relationship between histone acetylation and gene expression has been enhanced dramatically by the identification of proteins with intrinsic hist one acetylase and deacetylase activity, which led to a major paradigm shift in understanding of chromatin structure and transcription regulation.
Abstract: More than 30 years ago, Vincent Allfrey proposed that histone acetylation was associated with transcriptional activity in eukaryotic cells (Allfrey et al. 1964; Pogo et al. 1966). Subsequently, acetylated core histones were shown to preferentially associate with transcriptionally active chromatin (Sealy and Chalkley 1978; Vidali et al. 1978; Hebbes et al. 1988). Acetylation occurs at lysine residues on the amino-terminal tails of the histones, thereby neutralizing the positive charge of the histone tails and decreasing their affinity for DNA (Hong et al. 1993). As a consequence, histone acetylation alters nucleosomal conformation (Norton et al. 1989), which can increase the accessibility of transcriptional regulatory proteins to chromatin templates (Lee et al. 1993; Vettese-Dadey et al. 1996). Taken together, these observations suggested how histone acetylation could result in increased transcriptional activity in vivo. However, there was essentially no information about the cause and effect relationship between histone acetylation and transcriptional activity or about the underlying molecular mechanisms. A mechanistic and physiologically relevant connection between histone acetylation and transcriptional regulation was initially provided by two independent lines of evidence. First, yeast cells unable to acetylate the histone H4 tail because of mutations of the target lysine residues show altered patterns of transcription (Durrin et al. 1991). However, these mutations broadly affect chromatin structure in vivo, and hence are likely to influence other molecular processes involving DNA (e.g., DNA replication and repair, recombination, chromosome segregation). Second, treatment of mammalian cells with potent inhibitors of histone deacetylase activity such as trapoxin or trichostatin A resulted in increased expression of a variety of genes (Yoshida et al. 1995). However, these drugs might inhibit other cellular targets, and they affect a variety of cellular processes, including cell proliferation, apoptosis, differentiation, and DNA synthesis. Although these observations were suggestive, understanding of the relationship between chromatin structure and transcription regulation was hampered significantly by a lack of knowledge about the enzymes that acetylate and deacetylate histones. In the past 2 years, our understanding of the causal relationship between histone acetylation and gene expression has been enhanced dramatically by the identification of proteins with intrinsic histone acetylase and deacetylase activity (Brownell et al. 1996; for recent reviews, see Grunstein 1997; Pazin and Kadonaga 1997; Wade et al. 1997). Of particular significance, some of these enzymes had been identified previously as components of the RNA polymerase II (Pol II) transcription machinery itself, proteins that associate with transcriptional regulatory factors, or proteins that positively or negatively affect transcription in vivo. These discoveries have led to a major paradigm shift. It is now clear that chromatin structure and modification can not be viewed as a process that is independent of transcriptional initiation, that is, chromatin is not simply a structure that serves to compact DNA in the nucleus and provide a relatively passive substrate for the action of transcription factors. Instead, histone acetylases and deacetylases provide a critical link between chromatin structure and transcriptional output, and this link is now accessible to experimental intervention. This review will focus on molecular mechanisms by which histone acetylation affects transcriptional activity in living cells.
1,814 citations
"The language of covalent histone mo..." refers background in this paper
...Fuelled, in part, by the discovery of enzymes responsible for bringing about the steady-state balance of this modification—histone acetyltransferases (HATs) and histone deacetylase (HDACs)—compelling evidence has recently been provided that acetylation of specific lysine residues in the amino termini of the core histones plays a fundamental role in transcriptional regulatio...
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