Nucleosome Binding by the Bromodomain and PHD Finger of the Transcriptional Cofactor p300

Ragvin, Anja; Valvatne, Håvard; Erdal, Sigrid; Årskog, Vibeke; Tufteland, Katharina R.; Breen, Kamilla; Øyan, Anne Margrete; Eberharter, Anton; Gibson, Toby J.; Becker, Peter B.; Aasland, Rein

doi:10.1016/j.jmb.2004.01.051

Cited by 113 publications

(109 citation statements)

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“…Recently, a model was proposed where adjacent PHD and bromodomains both contact nucleosomes while at the same time interacting with each other. 42 Thus, BRD1 contains a number of motifs pointing towards a possible function as a transcriptional co-factor, which would be in accordance with the subcellular expression pattern observed.…”

Section: Discussionsupporting

confidence: 72%

Evidence implicating BRD1 with brain development and susceptibility to both schizophrenia and bipolar affective disorder

et al. 2006

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Linkage studies suggest that chromosome 22q12-13 may contain one or more shared susceptibility genes for schizophrenia (SZ) and bipolar affective disorder (BPD). In a Faeroese sample, we previously reported association between microsatellite markers located at 22q13.31-qtel and both disorders. The present study reports an association analysis across five genes (including 14 single nucleotide and two microsatellite polymorphisms) in this interval using a case-control sample of 162 BPD, 103 SZ patients and 200 controls. The bromodomain-containing 1 gene (BRD1), which encodes a putative regulator of transcription showed association with both disorders with minimal P-values of 0.0046 and 0.00001 for single marker and overall haplotype analysis, respectively. A specific BRD1 2-marker 'risk' haplotype showed a frequency of B10% in the combined case group versus B1% in controls (P-value 2.8 Â 10 À7 ). Expression analysis of BRD1 mRNA revealed widespread expression in mammalian brain tissue, which was substantiated by immunohistochemical detection of BRD1 protein in the nucleus, perikaryal cytosol and proximal dendrites of the neurons in the adult rat, rabbit and human CNS. Quantitative mRNA analysis in developing fetal pig brain revealed spatiotemporal differences with high expression at early embryonic stages, with intense nuclear and cytosolar immunohistochemical staining of the neuroepithelial layer and early neuroblasts, whilst more mature neurons at later embryonic stages had less nuclear staining. The results implicate BRD1 with SZ and BPD susceptibility and provide evidence that suggests a role for BRD1 in neurodevelopment.

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Section: Discussionsupporting

confidence: 72%

Evidence implicating BRD1 with brain development and susceptibility to both schizophrenia and bipolar affective disorder

et al. 2006

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“…Indeed, the tandem bromodomain-PHD finger of p300/CBP shows cooperative nucleosome binding activity 27 . Note in this case that the bromodomain of p300/CBP is capable of recognizing acetylated lysine residues on histones.…”

Section: Discussionmentioning

confidence: 99%

“…The tandem bromodomain-PHD finger of the human transcriptional coactivator p300/CBP has been shown to be interdependent in interactions with nucleosomes 27 . A more common, reversely connected motif, the PHD finger-bromodomain, is found in many chromatinassociated proteins including histone lysine methyl-transferase MLL1 (ref.…”

mentioning

confidence: 99%

Structural insights into human KAP1 PHD finger–bromodomain and its role in gene silencing

Zeng

Yap

Ivanov

et al. 2008

Nat Struct Mol Biol

118

117

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The tandem PHD finger-bromodomain, found in many chromatin-associated proteins, has an important role in gene silencing by the human co-repressor KRAB-associated protein 1 (KAP1). Here we report the three-dimensional solution structure of the tandem PHD finger-bromodomain of KAP1. The structure reveals a distinct scaffold unifying the two protein modules, in which the first helix, α Z , of an atypical bromodomain forms the central hydrophobic core that anchors the other three helices of the bromodomain on one side and the zinc binding PHD finger on the other. A comprehensive mutation-based structure-function analysis correlating transcriptional repression, ubiquitin-conjugating enzyme 9 (UBC9) binding and SUMOylation shows that the PHD finger and the bromodomain of KAP1 cooperate as one functional unit to facilitate lysine SUMOylation, which is required for KAP1 co-repressor activity in gene silencing. These results demonstrate a previously unknown unified function for the tandem PHD finger-bromodomain as an intramolecular small ubiquitin-like modifier (SUMO) E3 ligase for transcriptional silencing.Chemical modifications of chromatin on the DNA (for example, methylation of cytosine) and DNA-packing histones (for example, acetylation, methylation, phosphorylation, ubiquitination and SUMOylation) are important in the epigenetic control of gene transcription in response to physiological and environmental stimuli [1][2][3] . An emerging model suggests that there is an 'epigenetic code' embedded within chromatin to signify regions of distinct nuclear activities, such as heterochromatin formation or transcriptional activation [4][5][6] . It is thought that the epigenetic code is established by chromatin-modifying enzymes and interpreted by proteins that bind the chromatin in a modification-sensitive manner. The discovery of methyl-CpG binding domains 7 , bromodomains as acetyllysine binding The tandem bromodomain-PHD finger of the human transcriptional coactivator p300/CBP has been shown to be interdependent in interactions with nucleosomes 27 . A more common, reversely connected motif, the PHD finger-bromodomain, is found in many chromatinassociated proteins including histone lysine methyl-transferase MLL1 (ref. 28), Williams syndrome transcription factor (WSTF) in the chromatin-remodeling complex WINAC 29 , and the TIF1 family proteins (α, β, γ and δ; note that TIF1β is also known as KAP1 or TRIM28) 30 . This tandem PHD finger-bromodomain is also found in Sp140, a leukocytespecific protein in the nuclear body that is involved in the pathogenesis of acute promyelocytic leukemia and viral infection 31 . Mutations of PHD fingers, particularly those that disrupt zinc coordination, have been linked to tumor formation and genetic disorders 32 .More recently, it has been reported that the PHD finger of the human co-repressor KAP1 functions as a unique SUMO E3 ligase that is required for KAP1's gene transcription repression activity 33 .To understand its molecular function in gene silencing, we solved the three-dim...

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“…PHD fingers are found in multiple complexes that regulate chromatin structure; however, the function of the majority of these domains is unknown. The PHD fingers of the p300 histone acetyltransferase and ACF1, a subunit of an ATP-dependent nucleosome remodeling complex, are required for these proteins to bind histones (12,54), but whether this binding is dependent on the methylation state of the histones was not investigated. However, the fact that the binding of the ACF1 PHD fingers to histones was not dependent on the presence of the histone tails argues against this possibility for ACF1 (12).…”

Section: Discussionmentioning

confidence: 99%

“…Members of the ING family contain a PHD finger domain within their carboxyl termini (21). This zinc finger-like motif is found in various proteins involved in chromatin-mediated gene regulation (1), and several studies have implicated PHD fingers in mediating the interaction of chromatin-modifying factors with histones (12,54). Indeed, the Yng2p PHD finger is required for full activation of NuA4-dependent genes, suggesting that this motif is required for some aspect of HAT complex function (46).…”

Section: Yng1p Interacts With the Histone H3 Tail In Vivomentioning

confidence: 99%

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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Nucleosome Binding by the Bromodomain and PHD Finger of the Transcriptional Cofactor p300

Cited by 113 publications

References 53 publications

Evidence implicating BRD1 with brain development and susceptibility to both schizophrenia and bipolar affective disorder

Evidence implicating BRD1 with brain development and susceptibility to both schizophrenia and bipolar affective disorder

Structural insights into human KAP1 PHD finger–bromodomain and its role in gene silencing

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

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