The bromodomain of Gcn5p interacts in vitro with specific residues in the N terminus of histone H4 1 1Edited by T. Richmond

Ornaghi, Prisca; Ballario, Paola; Lena, Anna Maria; González, Alicia; Filetici, Patrizia

doi:10.1006/jmbi.1999.2577

Cited by 103 publications

(79 citation statements)

References 35 publications

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“…For example, many HATenzymes bind preferentially to acetylated peptides, in vitro binding assays, using their bromodomains. (84) More particularly, it has been found that the SAGA complex remains anchored to acetylated arrays of nucleosomes through a GCN5 bromodomain, even after removal of the transcription factor VP16, thus providing a self-perpetuating activating mark on chromatin domain. (33) In contrast the NuA4 complex, which lacks a bromodomain, is not retained following removal of the activators.…”

Section: Sant Domain and Atp-dependent Remodelling Enzymesmentioning

confidence: 99%

Do protein motifs read the histone code?

et al. 2005

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SummaryThe 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. The histone code hypothesis The packing of the eukaryotic genome into chromatin provides the means for compaction of the entire genome inside the nucleus. However, this packing restricts the access to DNA of the many regulatory proteins essential for biological processes like replication, transcription, DNA repair and recombination.(1)There are two mechanisms that can counterbalance the repressive nature of chromatin, allowing access to nucleosomal DNA: (i) covalent modification of histone tails like acetylation, methylation, phosphorylation and ubiquitination; (2)(3)(4)(5) and (ii) altering of the nucleosomal structure by enzymes utilising energy from ATP hydrolysis.In the early nineties, it was proposed that histone covalent modifications can work as recognition signals, directing the binding to chromatin of non-histone proteins that determine chromatin function. (7,8) More recently, it has been hypothesized that specific tail modifications and/or their combinations constitute a code, the histone code, that determines the transcriptional state of the genes. (9)(10)(11) According to this hypothesis, ''multiple histone modifications, acting in a combinatorial or sequential fashion on one or multiple tails, specify unique downstream functions''.In the last years, an increasing amount of experimental data has provided clear support for the different aspects of the histone code hypothesis, contributing to refine and improve it.(For review 12,13) One important point that has been addressed by different authors is the idea that the histone code must use combinations of modifications.(9) For example, H3 methylated at K9 could initiate chromatin condensation and silencing (14,15) but, in the context of methylated H3K4 and H4K20, methyl-K9 H3 helps to maintain ...

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Section: Sant Domain and Atp-dependent Remodelling Enzymesmentioning

confidence: 99%

Do protein motifs read the histone code?

et al. 2005

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“…A bromodomain is a motif present in a number of chromatin-modifying proteins including histone acetylases of the GNAT family, CBP͞p300, general transcription factors including TAFII250, and chromatin remodeling factors of the SWI͞SNF family (3,4). Structural analyses in vitro have shown that the bromodomain is composed of four ␣-helices and binds to acetylated lysines on histone H3 and H4, although with relatively low affinity (5)(6)(7)(8)(9). Based on these studies, the bromodomain has been proposed to act as a chromatin targeting module, deciphering histone acetylation codes (1,2,10).…”

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“…In addition to transcription, histone acetylation codes may play a role in cell growth, as H3 and H4 are transiently acetylated during replication (13)(14)(15). So far, however, studies on the interaction of bromodomains with acetylated histones have been limited to those of a few select proteins, such as PCAF, GCN5, and TAFII250 (5)(6)(7)9), and more recently yeast Bdf1 and Bdf2 (16,17). The latter two proteins belong to the BET family, whose members carry two tandem bromodomains (3,4).…”

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

Dey

Chitsaz

Abbasi

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

595

599

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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.A cetylation of lysines on histone tails is thought to form distinct histone codes that direct molecular processes important for transcription (1, 2). A bromodomain is a motif present in a number of chromatin-modifying proteins including histone acetylases of the GNAT family, CBP͞p300, general transcription factors including TAFII250, and chromatin remodeling factors of the SWI͞SNF family (3, 4). Structural analyses in vitro have shown that the bromodomain is composed of four ␣-helices and binds to acetylated lysines on histone H3 and H4, although with relatively low affinity (5-9). Based on these studies, the bromodomain has been proposed to act as a chromatin targeting module, deciphering histone acetylation codes (1, 2, 10). However, despite in vitro evidence, it has not been clear whether bromodomain proteins interact with acetylated chromatin in the native nuclear environment in vivo. Besides the question of in vivo interaction, it has not been clear whether differentially acetylated histones are distinguished by bromodomains. The latter question is of interest in view of the fact that bromodomains of different proteins have considerable structural diversity (3, 4). Furthermore, histone acetylation codes are likely to be diverse and translated into distinct processes, as individual lysines on histone H3 and H4 are acetylated in a highly specific and ordered fashion during transcription (11,12). In addition to transcription, histone acetylation codes may play a role in cell growth, as H3 and ...

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“…Consistent with this, several protein motifs have been identified that mediate the selective interaction of transcription-regulating complexes with specific histone modifications. The first such identified motif is the bromodomain, which preferentially interacts with acetylated histones (7,10,24,49,50,65). Bromodomains are found in a number of protein complexes, including components of the basal transcription machinery and chromatin remodeling complexes (20, 41), which may explain, in part, how histone acetylation can facilitate transcription.…”

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The Yng1p Plant Homeodomain Finger Is a Methyl-Histone Binding Module That Recognizes Lysine 4-Methylated Histone H3

Martin¹,

Baetz

Shi

et al. 2006

Molecular and Cellular Biology

145

114

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The ING (inhibitor of growth) protein family includes a group of homologous nuclear proteins that share a highly conserved plant homeodomain (PHD) finger domain at their carboxyl termini. Members of this family are found in multiprotein complexes that posttranslationally modify histones, suggesting that these proteins serve a general role in permitting various enzymatic activities to interact with nucleosomes. There are three members of the ING family in Saccharomyces cerevisiae: Yng1p, Yng2p, and Pho23p. Yng1p is a component of the NuA3 histone acetyltransferase complex and is required for the interaction of NuA3 with chromatin. To gain insight into the function of the ING proteins, we made use of a genetic strategy to identify genes required for the binding of Yng1p to histones. Using the toxicity of YNG1 overexpression as a tool, we showed that Yng1p interacts with the amino-terminal tail of histone H3 and that this interaction can be disrupted by loss of lysine 4 methylation within this tail. Additionally, we mapped the region of Yng1p required for overexpression of toxicity to the PHD finger, showed that this region capable of binding lysine 4-methylated histone H3 in vitro, and demonstrated that mutations of the PHD finger that abolish binding in vitro are no longer toxic in vivo. These results identify a novel function for the Yng1p PHD finger in promoting stabilization of the NuA3 complex at chromatin through recognition of histone H3 lysine 4 methylation.Chromatin structure can be regulated by the addition of posttranslational modifications to histones, including acetylation, methylation, phosphorylation, and ubiquitination. These modifications are thought to function by creating docking sites for factors which alter chromatin structure (27,58). Consistent with this, several protein motifs have been identified that mediate the selective interaction of transcription-regulating complexes with specific histone modifications. The first such identified motif is the bromodomain, which preferentially interacts with acetylated histones (7,10,24,49,50,65). Bromodomains are found in a number of protein complexes, including components of the basal transcription machinery and chromatin remodeling complexes (20, 41), which may explain, in part, how histone acetylation can facilitate transcription. Bromodomains are also found in a number of histone methyltransferases, suggesting that histone acetylation can mediate histone methylation (6). The ability of one histone modification to recruit another histone-modifying enzyme is a common recurring theme in chromatin research.A second motif which has been shown to bind modified histones is the chromodomain, which preferentially interacts with methylated lysines (19,52). Chromodomains are found in proteins involved in both the activation and silencing of transcription, consistent with the role of histone methylation in both events (31). Similar to bromodomains, chromodomains are found in chromatin remodeling complexes, histone acetyltransferases, and histone methyltransfer...

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The bromodomain of Gcn5p interacts in vitro with specific residues in the N terminus of histone H4 1 1Edited by T. Richmond

Cited by 103 publications

References 35 publications

Do protein motifs read the histone code?

Do protein motifs read the histone code?

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

The Yng1p Plant Homeodomain Finger Is a Methyl-Histone Binding Module That Recognizes Lysine 4-Methylated Histone H3

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