Stimulation of CREB Binding Protein Nucleosomal Histone Acetyltransferase Activity by a Class of Transcriptional Activators

Abstract

The transcriptional coactivator CREB binding protein (CBP) possesses intrinsic histone acetyltransferase (HAT) activity that is important for gene regulation. CBP binds to and cooperates with numerous nuclear factors to stimulate transcription, but it is unclear if these factors modulate CBP HAT activity. Our previous work showed that CBP interacts with the Epstein-Barr virus-encoded basic region zipper (b-zip) protein, Zta, and augments its transcriptional activity. Here we report that Zta strongly enhances CBP-mediated acetylation of nucleosomal histones. Zta stimulated the HAT activity of CBP that had been partially purified or immunoprecipitated from mammalian cells as well as from affinity-purified, baculovirus expressed CBP. Stimulation of nucleosome acetylation required the CBP HAT domain, the Zta DNA binding and transcription activation domain, and nucleosomal DNA. In addition to Zta, we found that two other b-zip proteins, NF-E2 and C/EBP␣, strongly stimulated nucleosomal HAT activity. In contrast, several CBP-binding proteins, including phospho-CREB, JUN/FOS, GATA-1, Pit-1, and EKLF, failed to stimulate HAT activity. These results demonstrate that a subset of transcriptional activators enhance the nucleosome-directed HAT activity of CBP and suggest that nuclear factors may regulate transcription by altering substrate recognition and/or the enzymatic activity of chromatin modifying coactivators.Eukaryotic gene expression is inhibited by higher order chromatin structures that limit the access of transcription factors to regulatory DNA sequences (reviewed in references 43, 45, and 67). These higher order structures are thought to be regulated by posttranslational modification of chromatin components (66). The acetylation of lysine residues in the core histone amino terminal tails is one chromatin modification that correlates with increased transcription activity (reviewed in references 36, 40, 56, 66, and 70). Several transcriptional coactivators possess intrinsic histone acetyltransferase (HAT) activity, including the CREB binding protein (CBP), its close relative p300, the SAGA-associated GCN5, the GCN5-related P/CAF, the MYST family protein Tip60, and the TATA-binding protein-associated factor TAF II 250 (7,15,35,39,59,61). Numerous transcriptional activators bind HAT-containing coactivators through interaction domains that are essential for transcription function (68). One important question is whether the coactivator HAT activity is constitutive or whether it can be modulated by interaction with transcriptional activators.CBP was isolated by virtue of its ability to bind the transcriptionally active phosphorylated form of CREB (34). Subsequently, CBP has been shown to function as a transcriptional coactivator for numerous cellular transcription factors, including the tumor suppressor p53, proto-oncoproteins c-JUN and c-MYB, nuclear hormone receptors, the hematopoietic transcription factors EKLF, GATA-1, and NF-E2, and the viral proteins, such as the adenovirus E1A, the simian virus 40 T antigen, the ...

A WW Domain-binding Motif within the Activation Domain of the Hematopoietic Transcription Factor NF-E2 Is Essential for Establishment of a Tissue-specific Histone Modification Pattern

“…NF-E2 might be required to activate the histone acetyltransferase activity of CBP/p300. Of relevance to this possibility is the report that NF-E2 activates histone acetyltransferase activity of CBP/p300 in vitro (62).…”

“…The association of CBP/p300 with HS2 in CB3 cells indicates that another factor, potentially GATA-1, recruits CBP/p300 to HS2 in this system. CBP/p300 occupancy of HS2 increases upon GATA-1 expression in GATA-1-null G1E cells (62). Nevertheless, CBP/p300 recruitment might be insufficient to convey an activation signal to the promoter.…”

Proteomic identification of the MYST domain histone acetyltransferase TIP60 (HTATIP) as a co-activator of the myeloid transcription factor C/EBPα

“…However, in-depth studies involving protein-protein interactions of C/EBPa with HATs are lacking. 11,13 In our efforts to identify interacting partners of C/EBPa utilizing mass spectrometry-based proteomics, 7,8 we identified TIP60 (HTATIP; Tat-interactive protein, 60 kDa), a MYST family HAT. The identification of TIP60 as a C/EBPa interacting partner is intriguing because of the role of TIP60 in transcriptional activation, DNA repair and histone acetylation.…”

Transcriptional Repression by Sumoylation of Epstein-Barr Virus BZLF1 Protein Correlates with Association of Histone Deacetylase

“…Repression by BZLF1 Sumoylation-It has been reported that BZLF1 activates viral gene expression by interacting with the CBP possessing histone transacetylase activity (11)(12)(13)(14)(15). Immunoprecipitation assays indicated that BZLF1 did associate with CBP, but the interaction between sumoylated BZLF1 and CBP was somehow attenuated (data not shown), suggesting that conjugation of SUMO molecule to BZLF1 protein might reduce its association with the CBP transcriptional co-activator.…”

“…It is reported that, in latently infected cells, the silent state of the virus genome is maintained, at least in part, by MEF2-mediated recruitment of HDAC proteins to the BZLF1 promoter region (10). Once BZLF1 protein is expressed, the viral transcriptional activator recruits cAMPresponse element-binding protein (CREB)-binding protein (CBP), a histone acetyltransferase, to BZLF1-responsive sequences to activate viral early promoters (11)(12)(13)(14)(15) followed by a coordinated cascade of viral lytic steps such as viral DNA replication, late gene expression, and progeny virus production. Thus, interplay between histone deacetylation and acetylation is associated with repression or activation of transcription, regulating latency and the replicative cycle of EBV.…”