The TAZ2 domain of CBP/p300 directs acetylation towards H3K27 within chromatin

Abstract

The closely related acetyltransferases CBP and p300 are key regulators of gene expression in metazoans. CBP/p300 acetylate several specific lysine residues within nucleosomes, including histone H3 lysine 27 (H3K27), a hallmark of active enhancers and promoters. However, it has remained largely unclear how specificity of CBP/p300 towards H3K27 is achieved. Here we show that the TAZ2 domain of CBP is required for efficient acetylation of H3K27, while curbing activity towards other lysine residues within nucleosomes. We find that TAZ2 is a sequence-independent DNA binding module, promoting interaction between CBP and nucleosomes, thereby enhancing enzymatic activity and regulating substrate specificity of CBP. TAZ2 is further required to stabilize CBP binding to chromatin in mouse embryonic stem cells, facilitating specificity towards H3K27 and modulating gene expression. These findings reveal a crucial role of TAZ2 in regulating H3K27ac, while highlighting the importance of correct site-specific acetylation for proper regulation of gene expression.

Structural insights into p300 regulation and acetylation-dependent genome organisation

“…Recent data indicate that p300 directly engages nucleosome core particles (NCPs) through its ZZ (Zhang et al, 2018) and TAZ2 domains (Sheahan et al, 2020). Would then TAZ2-engagement also orient NCPs with respect to the HAT active site and specify nucleosome acetylation patterns?…”

“…Would then TAZ2engagement also orient NCPs with respect to the HAT active site and specify nucleosome acetylation patterns? In accordance with this possibility, it has been shown that the TAZ2 domain is required for efficient acetylation of H3K27, while curbing activity towards other lysine residues within nucleosomes (Sheahan et al, 2020). To test this model, we generated homogeneous 'structure-grade' NCPs as shown by single particle cryoEM (Fig.…”

“…We conclude that the interaction of TF ADs with the TAZ2 domain allosterically regulates p300 HAT activation by relief of autoinhibition. Recent data indicate that p300 directly engages nucleosome core particles (NCPs) through its ZZ (Zhang et al, 2018) and TAZ2 domains (Sheahan et al, 2020). Would then TAZ2engagement also orient NCPs with respect to the HAT active site and specify nucleosome acetylation patterns?…”

“…4e). Recent data indicate that p300 directly engages nucleosome core particles (NCPs) through its ZZ 76 and TAZ2 domains 77 . Would then NCP engagement also activate p300?…”

Recognizing the Binding Pattern and Dissociation Pathways of the p300 Taz2-p53 TAD2 Complex

“… 9 , 10 In addition, the interaction between the CBP transcriptional adaptor zinc-binding 2 (Taz2) domain and nucleosomal DNA, specifically acetylating histone H3 lysine 27 (H3K27), is essential for activating the enhancers and promoters of target genes. 11 Similarly, p53, classified as the pioneer transcription factor, can also directly bind with nucleosomal DNA via the interaction between the N-terminal region (amino acid 1–93) and the histone H3–H4. 12 Therefore, designing chemotherapy drugs targeting CBP/p300 cofactors or p53 is a potential strategy in cancer therapy.…”